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Shao H, Chen M, Xiao Y, Xu L, Cao H, Hong B, Qian Y. Establishing a Risk Prediction Model for Nasopharyngeal Carcinoma Based on Anti-BNLF2b Serological Biomarkers: A Retrospective Study. Int J Med Sci 2025; 22:2165-2173. [PMID: 40303496 PMCID: PMC12035835 DOI: 10.7150/ijms.110758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Purpose: This study aims to establish a suitable risk prediction model of NPC in regions with relatively low-incidence in southern China. Methods: We retrospectively analysed the data of 198 patients with NPC and 398 healthy individuals admitted to The Second Affiliated Hospital, Zhejiang University School of Medicine, from February 2023 to October 2024. The levels of different serum biomarkers (P85-Ab, VCA-IgA, VCA-IgM, VCA-IgG, Rta-IgG and EA-IgA) were compared between patients with NPC and healthy individuals. Binary logistic regression was used to construct a risk prediction model for NPC, and ROC curves were plotted to evaluate the performance of the model. Results: Compared with healthy individuals, patients with NPC exhibited significantly elevated levels of EA-IgA (P < 0.001), Rta-IgG (P < 0.001), P85-Ab (P < 0.001) and VCA-IgA (χ2 = 262.25; P < 0.001). Binary logistic regression showed that P85-Ab (HR = 572.225; P < 0.001), VCA-IgA (HR = 31.877; P < 0.001) and Rta-IgG (HR = 10.670; P = 0.004) were independent risk factors for NPC. The AUC of P85-Ab combined with Rta-IgG and VCA-IgA for predicting the risk of NPC was 0.977 (95% CI: 0.959-0.988), which was greater than the AUC values of Rta-IgG and VCA-IgA (P < 0.01 for all). The combination of P85-Ab with Rta-IgG and VCA-IgA had a sensitivity of 91.36% and a specificity of 99.25%. Conclusion: P85-Ab combined with VCA-IgA and Rta-IgG is an optimal serological biomarker for the diagnosis of NPC in low-incidence regions in southern China.
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Affiliation(s)
- Hengrong Shao
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Mengting Chen
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Yufei Xiao
- Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Li Xu
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Huaquan Cao
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Bo Hong
- Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yun Qian
- Department of Clinical Laboratory, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
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Ding XB, Ren SY, Wen HZ, Zhang ZB, Ye JA, Pan WK, Ye JQ. A Bidirectional Mendelian Randomization Study on the Causal Relationship Between Epstein-Barr Virus Antibodies and Prostate Cancer Risk. Cancer Control 2025; 32:10732748251320842. [PMID: 40026212 PMCID: PMC11873887 DOI: 10.1177/10732748251320842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 01/19/2025] [Accepted: 01/30/2025] [Indexed: 03/04/2025] Open
Abstract
OBJECTIVES This study aims to examine the correlation between four distinct Epstein-Barr virus (EBV) antibodies (EA-D, EBNA-1, VCA-p18, and ZEBRA) and the likelihood of developing prostate cancer (PCa) using the Mendelian Randomization (MR) technique. The primary objective is to determine whether a causal relationship exists between these EBV antibodies and prostate cancer. METHODS Genome-wide association study (GWAS) data for EBV antibodies were sourced from the UK Biobank cohort, and prostate cancer data were obtained from the PRACTICAL consortium, which includes 79148 cases and 61106 controls. Univariable Mendelian Randomization (MR) analysis was conducted to evaluate the associations, while reverse Mendelian Randomization was employed to assess causality. Additionally, Multivariable Mendelian Randomization analysis was performed to identify independent risk factors. RESULTS Univariable MR analysis revealed significant associations between EBV EA-D (OR = 1.084, 95% CI = 1.012-1.160, IVW_P = 0.021) and EBNA-1 (OR = 1.086, 95% CI = 1.025-1.150, IVW_P = 0.005) antibodies and an increased risk of prostate cancer. Reverse MR analysis did not establish a causal relationship. Multivariable MR analysis identified the EBV EBNA-1 antibody as an independent risk factor for prostate cancer (OR = 1.095, 95% CI = 1.042-1.151, IVW_P = 0.00036). CONCLUSION The study highlights the association between EBV antibody levels, particularly EBNA-1, and prostate cancer risk, suggesting EBNA-1 as an independent risk factor. Future research is needed to elucidate the biological pathways linking EBV antibody levels to prostate cancer. These insights could be instrumental in developing targeted prevention strategies and therapeutic interventions for prostate cancer.
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Affiliation(s)
- Xiao-bo Ding
- Department of Ultrasound, Sir Run Run Shaw Hospital, Hangzhou, China
| | - Si-yan Ren
- Department of Radiation Oncology, Sir Run Run Shaw Hospital, Hangzhou, China
| | - He-zhi Wen
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhi-bin Zhang
- Department of Orthopedic Surgery, Longquan People’s Hospital, Lishui, China
| | - Jia-ang Ye
- Department of Stomatology, Jining Medical University, Jining, China
| | - Wen-kai Pan
- Department of Nuclear Medicine, Sir Run Run Shaw Hospital, Hangzhou, China
| | - Jia-qi Ye
- Department of Radiotherapy, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
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Chen WJ, Yu X, Lu YQ, Pfeiffer RM, Ling W, Xie SH, Wu ZC, Li XQ, Fan YY, Wu BH, Wei KR, Rao HL, Huang QH, Guo X, Sun Y, Ma J, Liu Q, Hildesheim A, Hong MH, Zeng YX, Ji MF, Liu Z, Cao SM. Impact of an Epstein-Barr Virus Serology-Based Screening Program on Nasopharyngeal Carcinoma Mortality: A Cluster-Randomized Controlled Trial. J Clin Oncol 2025; 43:22-31. [PMID: 39353160 DOI: 10.1200/jco.23.01296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 05/05/2024] [Accepted: 07/19/2024] [Indexed: 10/04/2024] Open
Abstract
PURPOSE Screening for nasopharyngeal carcinoma (NPC) has shown an improvement in early detection and survival rates of NPC in endemic regions. It is critical to evaluate whether NPC screening can reduce NPC-specific mortality in the population. METHODS Sixteen towns in Sihui and Zhongshan cities, China, were selected; eight were randomly allocated to the screening group and eight to the control group. Residents age 30-69 years with no history of NPC were included from January 1, 2008, to December 31, 2015. Residents in the screening towns were invited to undergo serum Epstein-Barr virus (EBV) viral capsid antigen/nuclear antigen 1-immunoglobulin A antibody tests; others received no intervention. The population was followed until December 31, 2019. Nonparametric tests and Poisson regression models were used to estimate the screening effect on NPC mortality, accounting for the cluster-randomized design. The trial is registered with ClinicalTrials.gov (identifier: NCT00941538). RESULTS A total of 174,943 residents in the screening group and 186,263 residents in the control group were included. NPC incidence and overall mortality were similar between the two groups. A total of 52,498 (30.0% of 174,943) residents participated in the serum EBV antibody test. The overall compliance rate for endoscopic examination and/or biopsies among baseline and ever-classified high-risk participants was 65.9% (1,110 of 1,685) and 67.6% (1,703 of 2,518), respectively. A significant 30% reduction in NPC mortality was observed in the screening group compared with the control group (standardized NPC-specific mortality rate of 8.2 NPC deaths per 1,000 person-years versus 12.5; adjusted rate ratio [RR], 0.70 [95% CI, 0.49 to 0.997]; P = .048). This benefit was most evident among individuals age 50 years and older (RR, 0.56 [95% CI, 0.37 to 0.85]; P = .007) compared with those younger than 50 years (RR, 0.96 [95% CI, 0.64 to 1.46]; P = .856). CONCLUSION In this 12-year trial, EBV antibody testing resulted in a significant reduction in NPC mortality.
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Affiliation(s)
- Wen-Jie Chen
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xia Yu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, China
| | | | - Ruth M Pfeiffer
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Wei Ling
- Sihui Cancer Institute, Sihui, China
| | - Shang-Hang Xie
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi-Cong Wu
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xue-Qi Li
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yu-Ying Fan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Biao-Hua Wu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, China
| | - Kuang-Rong Wei
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, China
| | - Hui-Lan Rao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | | | - Xiang Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Sun
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun Ma
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qing Liu
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Allan Hildesheim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
- Agencia Costarriciense de Investigaciones Biologicas, San Jose, Costa Rica
| | - Ming-Huang Hong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- Department of Clinical Research, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yi-Xin Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ming-Fang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, China
| | - Zhiwei Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Su-Mei Cao
- Department of Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, and Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
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Ma L, Wang TM, He YQ, Liao Y, Yan X, Yang DW, Wang RH, Li FJ, Jia WH, Feng L. Multiplex assays reveal anti-EBV antibody profile and its implication in detection and diagnosis of nasopharyngeal carcinoma. Int J Cancer 2024; 155:1874-1885. [PMID: 38894502 DOI: 10.1002/ijc.35061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 05/08/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024]
Abstract
Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression.
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Affiliation(s)
- Lin Ma
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Tong-Min Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yong-Qiao He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao Yan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Da-Wei Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Rui-Hua Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fa-Jun Li
- Guangdong Key Laboratory of Human Evolution and Archaeometry, Department of Anthropology, School of Sociology and Anthropology, Sun Yat-sen University, Guangzhou, China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Lin Feng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
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Warner BE, Patel J, Wang R, Adams-Haduch J, Gao YT, Koh WP, Wong KW, Chiang AKS, Yuan JM, Shair KHY. The Epstein-Barr Virus Nuclear Antigen 1 Variant Associated with Nasopharyngeal Carcinoma Defines the Sequence Criteria for Serologic Risk Prediction. Clin Cancer Res 2024; 30:5207-5217. [PMID: 39264275 PMCID: PMC11567791 DOI: 10.1158/1078-0432.ccr-24-1142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 07/18/2024] [Accepted: 09/10/2024] [Indexed: 09/13/2024]
Abstract
PURPOSE Antibodies to select Epstein-Barr virus proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against Epstein-Barr virus nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years before diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay. EXPERIMENTAL DESIGN Mammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A, which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using prediagnostic NPC sera from two independent cohorts in Singapore and Shanghai, the People's Republic of China. RESULTS At 95% sensitivity, 487V yielded a 94.9% specificity compared with 86.1% for 487A. EBNA1 deleted for the conserved glycine-alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390-641) showed lower specificity (84.8%) than the EBNA1 GAr-deleted construct (92.4%) at 95% sensitivity. CONCLUSIONS Although EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr, but with residues consistently detected in Southeast Asian NPC tumors, is optimized for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection.
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Affiliation(s)
- Benjamin E Warner
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Japan Patel
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Renwei Wang
- Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jennifer Adams-Haduch
- Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Woon-Puay Koh
- Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ka Wo Wong
- Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Alan K S Chiang
- Department of Pediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jian-Min Yuan
- Cancer Epidemiology and Prevention Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kathy H Y Shair
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Alsaadawe M, Radman BA, Long J, Alsaadawi M, Fang W, Lyu X. Epstein Barr virus: A cellular hijacker in cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189218. [PMID: 39549877 DOI: 10.1016/j.bbcan.2024.189218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/05/2024] [Accepted: 11/10/2024] [Indexed: 11/18/2024]
Abstract
Numerous studies have demonstrated the importance of the Epstein-Barr Virus (EBV), which was initially identified in 1964 while studying Burkitt's lymphoma, in the development of a number of cancers, including nasopharyngeal carcinoma, Hodgkin's lymphoma, Burkitt's lymphoma, and EBV-associated gastric carcinoma. Gammaherpesvirus EBV is extremely common; by adulthood, over 90 % of people worldwide have been infected. Usually, the virus causes a permanent latent infection in B cells, epithelial cells, and NK/T cells. It then contributes to oncogenesis by inhibiting apoptosis and promoting unchecked cell proliferation through its latent proteins, which include EBNA-1, LMP1, and LMP2A. Tumor progression further accelerated by EBV's capacity to transition between latent and lytic phases, especially in cases of nasopharyngeal carcinoma. Although our understanding of the molecular underpinnings of EBV has advanced, there are still difficulties in identifying latent infections and creating targeted therapeutics. To tackle EBV-associated malignancies, current research efforts are concentrated on developing vaccines, developing better diagnostic tools, and developing targeted treatments. In order to improve treatment approaches and lower the incidence of EBV-related cancers worldwide, more research into the relationship between EBV and immune evasion and cancer formation is necessary.
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Affiliation(s)
- Moyed Alsaadawe
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Al-Qadisiyah Education Directorate, Ministry of Education, Al-Qadisiyah, Iraq
| | - Bakeel A Radman
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Biology, College of Science and Education, Albaydha University, Albaydha, Yemen
| | - Jingyi Long
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Mohenned Alsaadawi
- Education College of Pure Science, Al-Muthanna University, Al-Muthanna, Iraq
| | - Weiyi Fang
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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Yang L, Kartsonaki C, Simon J, Yao P, Guo Y, Lv J, Walters RG, Chen Y, Fry H, Avery D, Yu C, Jin J, Mentzer AJ, Allen N, Butt J, Hill M, Li L, Millwood IY, Waterboer T, Chen Z. Prospective evaluation of the relevance of Epstein-Barr virus antibodies for early detection of nasopharyngeal carcinoma in Chinese adults. Int J Epidemiol 2024; 53:dyae098. [PMID: 39008896 PMCID: PMC11249388 DOI: 10.1093/ije/dyae098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/10/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV) is a major cause of nasopharyngeal carcinoma (NPC) and measurement of different EBV antibodies in blood may improve early detection of NPC. Prospective studies can help assess the roles of different EBV antibodies in predicting NPC risk over time. METHODS A case-cohort study within the prospective China Kadoorie Biobank of 512 715 adults from 10 (including two NPC endemic) areas included 295 incident NPC cases and 745 subcohort participants. A multiplex serology assay was used to quantify IgA and IgG antibodies against 16 EBV antigens in stored baseline plasma samples. Cox regression was used to estimate adjusted hazard ratios (HRs) for NPC and C-statistics to assess the discriminatory ability of EBV-markers, including two previously identified EBV-marker combinations, for predicting NPC. RESULTS Sero-positivity for 15 out of 16 EBV-markers was significantly associated with higher NPC risk. Both IgA and IgG antibodies against the same three EBV-markers showed the most extreme HRs, i.e. BGLF2 (IgA: 124.2 (95% CI: 63.3-243.9); IgG: 8.6 (5.5-13.5); LF2: [67.8 (30.0-153.1), 10.9 (7.2-16.4)]); and BFRF1: 26.1 (10.1-67.5), 6.1 (2.7-13.6). Use of a two-marker (i.e. LF2/BGLF2 IgG) and a four-marker (i.e. LF2/BGLF2 IgG and LF2/EA-D IgA) combinations yielded C-statistics of 0.85 and 0.84, respectively, which persisted for at least 5 years after sample collection in both endemic and non-endemic areas. CONCLUSIONS In Chinese adults, plasma EBV markers strongly predict NPC occurrence many years before clinical diagnosis. LF2 and BGLF2 IgG could identify NPC high-risk individuals to improve NPC early detection in community and clinical settings.
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Affiliation(s)
- Ling Yang
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Christiana Kartsonaki
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Julia Simon
- Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Pang Yao
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Yu Guo
- National Center for Cardiovascular Diseases, Fuwai Hospital Chinese Academy of Medical Sciences, Beijing, China
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Peking University, Beijing, China
| | - Robin G Walters
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Yiping Chen
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Hannah Fry
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Daniel Avery
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Peking University, Beijing, China
| | | | | | - Naomi Allen
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Julia Butt
- Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hill
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Centre, Beijing, China
- Peking University Center for Public Health and Epidemic Preparedness & Response, Peking University, Beijing, China
| | - Iona Y Millwood
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Tim Waterboer
- Infections and Cancer Epidemiology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Zhengming Chen
- Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
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8
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Chen Y, Kincaid RP, Bastin K, Fachko DN, Skalsky RL. MicroRNA-focused CRISPR/Cas9 screen identifies miR-142 as a key regulator of Epstein-Barr virus reactivation. PLoS Pathog 2024; 20:e1011970. [PMID: 38885264 PMCID: PMC11213311 DOI: 10.1371/journal.ppat.1011970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 06/28/2024] [Accepted: 05/27/2024] [Indexed: 06/20/2024] Open
Abstract
Reactivation from latency plays a significant role in maintaining persistent lifelong Epstein-Barr virus (EBV) infection. Mechanisms governing successful activation and progression of the EBV lytic phase are not fully understood. EBV expresses multiple viral microRNAs (miRNAs) and manipulates several cellular miRNAs to support viral infection. To gain insight into the host miRNAs regulating transitions from EBV latency into the lytic stage, we conducted a CRISPR/Cas9-based screen in EBV+ Burkitt lymphoma (BL) cells using anti-Ig antibodies to crosslink the B cell receptor (BCR) and induce reactivation. Using a gRNA library against >1500 annotated human miRNAs, we identified miR-142 as a key regulator of EBV reactivation. Genetic ablation of miR-142 enhanced levels of immediate early and early lytic gene products in infected BL cells. Ago2-PAR-CLIP experiments with reactivated cells revealed miR-142 targets related to Erk/MAPK signaling, including components directly downstream of the B cell receptor (BCR). Consistent with these findings, disruption of miR-142 enhanced SOS1 levels and Mek phosphorylation in response to surface Ig cross-linking. Effects could be rescued by inhibitors of Mek (cobimetinib) or Raf (dabrafenib). Taken together, these results show that miR-142 functionally regulates SOS1/Ras/Raf/Mek/Erk signaling initiated through the BCR and consequently, restricts EBV entry into the lytic cycle.
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Affiliation(s)
- Yan Chen
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America
| | - Rodney P. Kincaid
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America
| | - Kelley Bastin
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America
| | - Devin N. Fachko
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America
| | - Rebecca L. Skalsky
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States of America
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9
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Yang DW, Miller JA, Xue WQ, Tang M, Lei L, Zheng Y, Diao H, Wang TM, Liao Y, Wu YX, Zheng XH, Zhou T, Li XZ, Zhang PF, Chen XY, Yu X, Li F, Ji M, Sun Y, He YQ, Jia WH. Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study. Front Public Health 2024; 12:1375533. [PMID: 38756891 PMCID: PMC11097958 DOI: 10.3389/fpubh.2024.1375533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 04/18/2024] [Indexed: 05/18/2024] Open
Abstract
Background Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.
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Affiliation(s)
- Da-Wei Yang
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jacob A. Miller
- Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, United States
| | - Wen-Qiong Xue
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | | | - Lin Lei
- Shenzhen Center for Chronic Disease Control, Shenzhen, China
| | - Yuming Zheng
- Wuzhou Red Cross Hospital, Wuzhou, Guangxi, China
| | - Hua Diao
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Tong-Min Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Liao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan-Xia Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao-Hui Zheng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ting Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xi-Zhao Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Pei-Fen Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xue-Yin Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xia Yu
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, China
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, China
| | - Ying Sun
- Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yong-Qiao He
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wei-Hua Jia
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China
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10
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Zhou F, Wang W, Xu R, Liu L, Lin T, He L, Tang L, Wang X, He Y. Unraveling the mechanism of Yiqi Jiedu formula against nasopharyngeal carcinoma: An investigation integrating network pharmacology, serum pharmacochemistry, and metabolomics. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117343. [PMID: 37879509 DOI: 10.1016/j.jep.2023.117343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 10/22/2023] [Indexed: 10/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yiqi Jiedu formula (YQJDF), rooted in the traditional Chinese medicinal principle of "tonifying qi and detoxifying", is remarkably efficacious in the clinical treatment of nasopharyngeal carcinoma (NPC). Previous studies have shed light on some of its anti-NPC effects and mechanisms, but the responsible pharmacological substances and their precise mechanisms of action remain unclear. AIM OF THE STUDY The purpose of this study was to identify components of YQJDF that entered the bloodstream and to investigate their mechanisms of action against NPC through network pharmacology and serum metabolomics. MATERIAL AND METHODS Components of YQJDF in serum were identified using liquid chromatography-tandem mass spectrometry. With these serum species as the focus of our research, network pharmacology analysis was used to identify active compounds and target genes that might mediate the efficacy of YQJDF in the treatment of NPC. Following establishment of an NPC xenograft model in nude mice, a non-targeted metabolomics approach was adopted to identify significant serum metabolites and metabolic pathways influenced by YQJDF. RESULTS Thirty-six components of YQJDF were identified, primarily consisting of alkaloids, phenylpropanoids, and flavonoids. Notably, pathways such as PI3K/AKT, factors associated with Epstein-Barr virus infection, IL-17 signaling, and lipid metabolism, were highlighted as potential therapeutic targets of YQJDF during NPC treatment. Additionally, our findings suggested that YQJDF modified the metabolism of arginine and proline in the serum of mice bearing nasopharyngeal tumor grafts. CONCLUSIONS This study identified the primary active components of YQJDF, highlighting its holistic role in the treatment of NPC through multiple targets and pathways. Furthermore, our findings provided a roadmap for future research into the mechanism of YQJDF in the therapy of NPC, setting the stage for its clinical application.
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Affiliation(s)
- Fangliang Zhou
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Wen Wang
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Runshi Xu
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Liu Liu
- Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Ting Lin
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Key Lab for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Lan He
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China; The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China
| | - Le Tang
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China
| | - Xianwen Wang
- Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China; The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, 410007, China.
| | - Yingchun He
- Hunan University of Chinese Medicine, Changsha, 410208, China; Hunan Provincial Engineering and Technological Research Center for Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Chinese Medicine and Protecting Visual Function, Hunan University of Chinese Medicine, Changsha, 410208, China.
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11
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Polz A, Morshed K, Drop B, Drop A, Polz-Dacewicz M. Serum Anti-Zta and Anti-LMP1 Antibodies in Oropharyngeal Cancer Related to Epstein-Barr Virus-Diagnostic Usefulness. Cancers (Basel) 2024; 16:341. [PMID: 38254830 PMCID: PMC10814749 DOI: 10.3390/cancers16020341] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND The role of the Epstein-Barr virus (EBV), the first known human oncogenic virus, in the development of nasopharyngeal cancer (NPC) is already well documented. There are few studies in the available scientific literature on oropharyngeal cancer associated with EBV infection. Due to the lack of an effective vaccine against EBV, it is necessary to search for new markers for the early diagnosis and prognosis of this disease. The aim of current study was to determine the usefulness of anti-Zta and anti-LMP1 antibodies as diagnostic and prognostic markers in EBV positive OPSCC patients. METHODS For this purpose, experiments were carried out to determine both the prevalence and level of EBVCA, EBNA1, EA, Zta, and LMP1 antibodies in serum patients depending on histological differentiation-grading and TNM classification (ELISA assay). RESULTS Based on the obtained results, we showed that OPSCC EBV positive patients are characterized by a higher level of anti-Zta antibodies than in the EBV negative group. Their level depended on the clinical stage. Moreover, a ROC analysis confirmed the diagnostic accuracy of anti-Zta antibodies. CONCLUSIONS Anti-Zta and anti-LMP1 antibodies may be useful in the diagnosis of OPSCC. It seems that combined antibody testing should be performed to increase diagnostic accuracy.
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Affiliation(s)
- Anna Polz
- Genomed S.A., 02-971 Warsaw, Poland;
| | - Kamal Morshed
- Department of Otolaryngology Head and Neck Cancer, University of Technology and Humanities in Radom, 26-600 Radom, Poland;
| | - Bartłomiej Drop
- Department of Computer Science and Medical Statistics with the e-Health Laboratory, 20-090 Lublin, Poland;
| | - Andrzej Drop
- 1st Department of Medical Radiology, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Małgorzata Polz-Dacewicz
- Department of Virology with Viral Diagnostics Laboratory, Medical University of Lublin, 20-093 Lublin, Poland
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12
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Melouli H, Khenchouche A, Taibi-Zidouni F, Salma D, Aoudia N, Djennaoui D, Sahraoui T, Benyahia S, El Kebir FZ. A Distinct Anti-EBV DNase Profile in Patients with Undifferentiated Nasopharyngeal Carcinoma Compared to Classical Antigens. Viruses 2023; 15:2158. [PMID: 38005835 PMCID: PMC10675439 DOI: 10.3390/v15112158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 09/17/2023] [Accepted: 10/08/2023] [Indexed: 11/26/2023] Open
Abstract
Nasopharyngeal cancer (NPC) is a prevalent type of cancer that often takes the form of undifferentiated carcinoma in the Maghreb region. It affects people of all ages. NPC diagnosis, mainly based on detecting Epstein-Barr virus (EBV), has not been well evaluated in North Africa. We compared the classical EBV serological tests using indirect immunofluorescence to the detection of EBV DNase antibodies by immunoblot in Algerian NPC patients. Significant variations were observed among different age groups of patients regarding the presence of VCA-IgA antibodies (0-14 and ≥30 years old, p < 0.0001; 15-19 and ≥30 years old, p < 0.01) and EA-IgA (0-14 and ≥30 years old, p < 0.01; 15-29 and ≥30 years old, p < 0.05). Differences were also noted in the titers of IgA anti-VCA and anti-EA antibodies across the three age groups. Some patients under the age of 30 with detectable IgG anti-VCA antibodies had undetectable IgA anti-VCA antibodies. These patients had a strong anti-DNase IgA response. However, older individuals had a higher level of anti-DNase IgG. Before treatment, children had strong DNase reactivity as indicated by specific IgA antibodies. Young adults had high IgA anti-DNase response, but the elderly (90.9%) had a lower response for these antibodies. Following therapy, the children retained high levels of IgA anti-DNase antibodies, and 66% of the young adults demonstrated robust antibody reactivity against DNase. In contrast, IgG responses to anti-DNase were low in children. This study demonstrated the utility of anti-DNase responses in the diagnosis and prognosis of NPC.
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Affiliation(s)
- Hamid Melouli
- Viral Oncogenesis Laboratory, Pasteur Institute of Algeria, Algiers 16000, Algeria; (H.M.)
| | - Abdelhalim Khenchouche
- Laboratory of Applied Biochemistry, Ferhat Abbas, Setif 1 University, Setif 19000, Algeria
| | - Fouzia Taibi-Zidouni
- Viral Oncogenesis Laboratory, Pasteur Institute of Algeria, Algiers 16000, Algeria; (H.M.)
| | - Dahmani Salma
- Viral Oncogenesis Laboratory, Pasteur Institute of Algeria, Algiers 16000, Algeria; (H.M.)
| | - Nassim Aoudia
- Viral Oncogenesis Laboratory, Pasteur Institute of Algeria, Algiers 16000, Algeria; (H.M.)
| | - Djamel Djennaoui
- Otorhinolaryngology Department, Mustapha Pacha Hospital, Algiers 16000, Algeria
| | - Tewfik Sahraoui
- Laboratory of Developmental Biology and Differentiation, Es-Sénia University, Oran 31000, Algeria
| | - Samir Benyahia
- Otorhinolaryngology Department, Mustapha Pacha Hospital, Algiers 16000, Algeria
| | - Fatima Zohra El Kebir
- Laboratory of Developmental Biology and Differentiation, Es-Sénia University, Oran 31000, Algeria
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13
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Low YH, Loh CJL, Peh DYY, Chu AJM, Han S, Toh HC. Pathogenesis and therapeutic implications of EBV-associated epithelial cancers. Front Oncol 2023; 13:1202117. [PMID: 37901329 PMCID: PMC10600384 DOI: 10.3389/fonc.2023.1202117] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 09/07/2023] [Indexed: 10/31/2023] Open
Abstract
Epstein-Barr virus (EBV), one of the most common human viruses, has been associated with both lymphoid and epithelial cancers. Undifferentiated nasopharyngeal carcinoma (NPC), EBV associated gastric cancer (EBVaGC) and lymphoepithelioma-like carcinoma (LELC) are amongst the few common epithelial cancers that EBV has been associated with. The pathogenesis of EBV-associated NPC has been well described, however, the same cannot be said for primary pulmonary LELC (PPLELC) owing to the rarity of the cancer. In this review, we outline the pathogenesis of EBV-associated NPC and EBVaGCs and their recent advances. By drawing on similarities between NPC and PPLELC, we then also postulated the pathogenesis of PPLELC. A deeper understanding about the pathogenesis of EBV enables us to postulate the pathogenesis of other EBV associated cancers such as PPLELC.
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Affiliation(s)
- Yi Hua Low
- Duke-NUS Medical School, Singapore, Singapore
| | | | - Daniel Yang Yao Peh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Axel Jun Ming Chu
- Singapore Health Services Internal Medicine Residency Programme, Singapore, Singapore
| | - Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
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14
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Sabourin KR, Mugisha J, Asiki G, Nalwoga A, Labo N, Miley W, Beyer R, Rochford R, Johnston TW, Newton R, Whitby D. Epstein-Barr virus (EBV) antibody changes over time in a general population cohort in rural Uganda, 1992-2008. Infect Agent Cancer 2023; 18:55. [PMID: 37775773 PMCID: PMC10543268 DOI: 10.1186/s13027-023-00534-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 09/12/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV) infection is ubiquitous and in sub-Saharan Africa, occurs early in life. In a population-based rural African cohort, we leveraged historical samples from the General Population Cohort (GPC) in Uganda to examine the epidemiology of infection with EBV over time, in the era of HIV. METHODS We used 9024 serum samples collected from the GPC in 1992, 2000, 2008, from 7576 participants across the age range (0-99 years of age) and tested for anti-EBV immunoglobulin G (IgG) antibodies to EAd, VCA, and EBNA-1 using a multiplex bead-based assay. The related gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity was also determined by detection of anti-KSHV IgG antibodies to K8.1 or ORF73 measured by recombinant protein enzyme-linked immunosorbent assay. Data on sex, age, and HIV serostatus were also collected. EBV seropositivity was modeled with age (excluding those under one year, who may have had maternal antibodies), sex, HIV serostatus, and KSHV serostatus using generalized linear mixed effects models to produce beta estimates. RESULTS More than 93% of children were EBV seropositive by one year of age. EBV seropositivity was significantly associated with KSHV seropositivity. Anti-EBNA-1 antibody levels decreased with increasing age and were lower on average in people living with HIV. In general, anti-EAd antibody levels increased with age, were higher in males and KSHV seropositive persons, but decreased over calendar time. Anti-VCA antibody levels increased with age and with calendar time and were higher in KSHV seropositive persons but lower in males. CONCLUSIONS This is the first study to identify factors associated with EBV antibodies across the entire life-course in rural sub-Saharan Africa. Consistent with other studies, EBV was near ubiquitous in the population by age one year. Patterns of antibodies show changes by age, sex and calendar time, but no association with HIV was evident, suggesting no relationship between EBV sero-epidemiology and the spread of HIV in the population over time in Uganda.
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Affiliation(s)
- Katherine R Sabourin
- Department of Immunology and Microbiology, CU School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, RC1N P18-9403D, Aurora, CO, 80045, USA.
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda.
| | - Joseph Mugisha
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Gershim Asiki
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- The African Population and Health Research Center, Nairobi, Kenya
| | - Angela Nalwoga
- Department of Immunology and Microbiology, CU School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, RC1N P18-9403D, Aurora, CO, 80045, USA
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Nazzarena Labo
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Wendell Miley
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Rachel Beyer
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Rosemary Rochford
- Department of Immunology and Microbiology, CU School of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, RC1N P18-9403D, Aurora, CO, 80045, USA
| | | | - Robert Newton
- UK Medical Research Council/ Uganda Virus Research Institute and London School of Health and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
- University of York, York, UK
| | - Denise Whitby
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
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15
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Budiningsih I, Verkuijlen SA, Dachlan YP, Arfijanto MV, Hadi U, Middeldorp JM. EBV-IgA antibody responses in endemic and nonendemic populations with nasopharyngeal carcinoma: tumour marker prognostication study and a cross-sectional study. Ann Med Surg (Lond) 2023; 85:4394-4403. [PMID: 37663720 PMCID: PMC10473314 DOI: 10.1097/ms9.0000000000000963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/10/2023] [Indexed: 09/05/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is the most prevalent head and neck cancer in Indonesia, with 100% Epstein-Barr virus (EBV) infection in tumor cells. NPC is rare in the Netherlands. The involvement of EBV in NPC pathogenesis is reflected by early onset aberrant IgA antibody responses to various EBV proteins. Screening for elevated EBV-IgA levels is proposed for NPC risk assessment in endemic countries but is poorly studied in nonendemic regions. This study analyzed the overall diversity (immunoblot) as well as the prevalence and normalized levels of IgA responses to immunodominant peptide epitopes of EBV proteins VCA P18, EBNA 1, and Zebra (Zta) (N-terminus, P 125, P 130, full-length recombinant Zebra) in Indonesian (n=50) and Dutch (n=50) patients with NPC. The results confirmed that elevated levels of IgA-VCA P18 and IgA-EBNA 1 were found in both NPC populations, but that IgA-Zta was more variable. IgA-Zta responses were more pronounced in Indonesian NPC cases, reflecting more frequent EBV reactivation overall. IgA-VCA P18 and IgA-EBNA are independent tumor markers and are both necessary for NPC risk assessment. Overall, these results confirmed the diagnostic benefit of combined IgA-VCA P18/-EBNA 1 testing for NPC risk assessment in endemic and nonendemic populations.
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Affiliation(s)
- Insani Budiningsih
- Doctoral Program of Medical Science, Faculty of Medicine
- Department of Pathology, Vrije Universiteit Amsterdam Amsterdam, The Netherlands
| | | | - Yoes P. Dachlan
- Department of Parasitology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | | | - Usman Hadi
- Department of Internal Medicine, Dr. Soetomo Hospital, School of Medicine
| | - Jaap M. Middeldorp
- Department of Pathology, Vrije Universiteit Amsterdam Amsterdam, The Netherlands
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16
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Lian M. Combining Epstein-Barr virus antibodies for early detection of nasopharyngeal carcinoma: A meta-analysis. Auris Nasus Larynx 2023; 50:430-439. [PMID: 36241564 DOI: 10.1016/j.anl.2022.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/21/2022] [Accepted: 09/27/2022] [Indexed: 04/03/2023]
Abstract
OBJECTIVE Epstein-Barr virus-related antibody seromarkers including VCA-IgA, EA-IgA, EBNA1-IgA, and Rta-IgG are used as markers for the detection of nasopharyngeal carcinoma (NPC). This meta-analysis was conducted to evaluate the diagnostic performance of their use in combined assays. METHODS Computerized searching of five electronic databases, supplemented by manual searching methods, was performed to identify pertinent articles. Diagnostic accuracy parameters, including sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC), were calculated with corresponding 95% confidence intervals (CIs). RESULTS Twenty-one studies with 4753 NPC cases and 31875 non-NPC controls were included. The pooled sensitivities for VCA-IgA+EA-IgA, VCA-IgA+EBNA1-IgA, VCA-IgA+Rta-IgG, and VCA-IgA+ EA-IgA+Rta-IgG were 0.89, 0.93, 0.94, and 0.94, respectively. Pooled specificities were 0.89, 0.88, 0.90, and 0.95, respectively. The PLRs were 8.1, 7.6, 9.4, and 17.4, respectively. Pooled NLRs were 0.12, 0.08, 0.07, and 0.07, respectively. Pooled DORs were 66, 95, 135, and 261, respectively. Pooled AUCs were 0.94, 0.96, 0.97, and 0.94, respectively. CONCLUSION These four combined assays based on EBV-related antibodies show diagnostic accuracy. The three-marker assay of VCA-IgA, EA IgA, and Rta-IgG has the best performance. Given the aspect of cost-benefit, VCA-IgA combined with EBNA1-IgA or Rta-IgG could become the preferred serodiagnostic strategy for NPC screening and early diagnosis.
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Affiliation(s)
- Mei Lian
- Department of Otorhinolaryngology, Tianjin Fifth Central Hospital, No.41 Zhejiang Road, Binhai New Area, Tianjin, 300450, China.
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17
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Tan H, Gong Y, Liu Y, Long J, Luo Q, Faleti OD, Lyu X. Advancing therapeutic strategies for Epstein-Barr virus-associated malignancies through lytic reactivation. Biomed Pharmacother 2023; 164:114916. [PMID: 37229802 DOI: 10.1016/j.biopha.2023.114916] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/17/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023] Open
Abstract
Epstein-Barr virus (EBV) is a widespread human herpes virus associated with lymphomas and epithelial cell cancers. It establishes two separate infection phases, latent and lytic, in the host. Upon infection of a new host cell, the virus activates several pathways, to induce the expression of lytic EBV antigens and the production of infectious virus particles. Although the carcinogenic role of latent EBV infection has been established, recent research suggests that lytic reactivation also plays a significant role in carcinogenesis. In this review, we summarize the mechanism of EBV reactivation and recent findings about the role of viral lytic antigens in tumor formation. In addition, we discuss the treatment of EBV-associated tumors with lytic activators and the targets that may be therapeutically effective in the future.
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Affiliation(s)
- Haiqi Tan
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Yibing Gong
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Yi Liu
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Jingyi Long
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Qingshuang Luo
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China
| | - Oluwasijibomi Damola Faleti
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China; Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, 999000, Hong Kong Special Administrative Region of China
| | - Xiaoming Lyu
- Department of Laboratory Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510630, China.
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18
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Xie C, Zhong LY, Bu GL, Zhao GX, Yuan BY, Liu YT, Sun C, Zeng MS. Anti-EBV antibodies: Roles in diagnosis, pathogenesis, and antiviral therapy. J Med Virol 2023; 95:e28793. [PMID: 37212266 DOI: 10.1002/jmv.28793] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/02/2023] [Accepted: 05/03/2023] [Indexed: 05/23/2023]
Abstract
Epstein-Barr virus (EBV) infection is prevalent in global population and associated with multiple malignancies and autoimmune diseases. During the infection, EBV-harbored or infected cell-expressing antigen could elicit a variety of antibodies with significant role in viral host response and pathogenesis. These antibodies have been extensively evaluated and found to be valuable in predicting disease diagnosis and prognosis, exploring disease mechanisms, and developing antiviral agents. In this review, we discuss the versatile roles of EBV antibodies as important biomarkers for EBV-related diseases, potential driving factors of autoimmunity, and promising therapeutic agents for viral infection and pathogenesis.
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Affiliation(s)
- Chu Xie
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Lan-Yi Zhong
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Guo-Long Bu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Ge-Xin Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Bo-Yu Yuan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Yuan-Tao Liu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Cong Sun
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
- Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou, China
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19
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Myers JE, Schaal DL, Nkadi EH, Ward BJH, Bienkowska-Haba M, Sapp M, Bodily JM, Scott RS. Retinoblastoma Protein Is Required for Epstein-Barr Virus Replication in Differentiated Epithelia. J Virol 2023; 97:e0103222. [PMID: 36719239 PMCID: PMC9972952 DOI: 10.1128/jvi.01032-22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/20/2022] [Indexed: 02/01/2023] Open
Abstract
Coinfection of human papillomavirus (HPV) and Epstein-Barr virus (EBV) has been detected in oropharyngeal squamous cell carcinoma. Although HPV and EBV replicate in differentiated epithelial cells, we previously reported that HPV epithelial immortalization reduces EBV replication within organotypic raft culture and that the HPV16 oncoprotein E7 was sufficient to inhibit EBV replication. A well-established function of HPV E7 is the degradation of the retinoblastoma (Rb) family of pocket proteins (pRb, p107, and p130). Here, we show that pRb knockdown in differentiated epithelia and EBV-positive Burkitt lymphoma (BL) reduces EBV lytic replication following de novo infection and reactivation, respectively. In differentiated epithelia, EBV immediate early (IE) transactivators were expressed, but loss of pRb blocked expression of the early gene product, EA-D. Although no alterations were observed in markers of epithelial differentiation, DNA damage, and p16, increased markers of S-phase progression and altered p107 and p130 levels were observed in suprabasal keratinocytes after pRb knockdown. In contrast, pRb interference in Akata BX1 Burkitt lymphoma cells showed a distinct phenotype from differentiated epithelia with no significant effect on EBV IE or EA-D expression. Instead, pRb knockdown reduced the levels of the plasmablast differentiation marker PRDM1/Blimp1 and increased the abundance of c-Myc protein in reactivated Akata BL with pRb knockdown. c-Myc RNA levels also increased following the loss of pRb in epithelial rafts. These results suggest that pRb is required to suppress c-Myc for efficient EBV replication in BL cells and identifies a mechanism for how HPV immortalization, through degradation of the retinoblastoma pocket proteins, interferes with EBV replication in coinfected epithelia. IMPORTANCE Terminally differentiated epithelium is known to support EBV genome amplification and virion morphogenesis following infection. The contribution of the cell cycle in differentiated tissues to efficient EBV replication is not understood. Using organotypic epithelial raft cultures and genetic interference, we can identify factors required for EBV replication in quiescent cells. Here, we phenocopied HPV16 E7 inhibition of EBV replication through knockdown of pRb. Loss of pRb was found to reduce EBV early gene expression and viral replication. Interruption of the viral life cycle was accompanied by increased S-phase gene expression in postmitotic keratinocytes, a process also observed in E7-positive epithelia, and deregulation of other pocket proteins. Together, these findings provide evidence of a global requirement for pRb in EBV lytic replication and provide a mechanistic framework for how HPV E7 may facilitate a latent EBV infection through its mediated degradation of pRb in copositive epithelia.
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Affiliation(s)
- Julia E. Myers
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Danielle L. Schaal
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Ebubechukwu H. Nkadi
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - B. J. H. Ward
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Malgorzata Bienkowska-Haba
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Martin Sapp
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Jason M. Bodily
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
| | - Rona S. Scott
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
- Center for Applied Immunology and Pathological Processes, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA
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20
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Liao Y, Zhang JB, Lu LX, Jia YJ, Zheng MQ, Debelius JW, He YQ, Wang TM, Deng CM, Tong XT, Xue WQ, Cao LJ, Wu ZY, Yang DW, Zheng XH, Li XZ, Wu YX, Feng L, Ye W, Mu J, Jia WH. Oral Microbiota Alteration and Roles in Epstein-Barr Virus Reactivation in Nasopharyngeal Carcinoma. Microbiol Spectr 2023; 11:e0344822. [PMID: 36645283 PMCID: PMC9927204 DOI: 10.1128/spectrum.03448-22] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/16/2022] [Indexed: 01/17/2023] Open
Abstract
Microbiota has recently emerged as a critical factor associated with multiple malignancies. Nasopharyngeal carcinoma (NPC) is highly associated with Epstein-Barr virus (EBV); the oncovirus resides and is transmitted in the oral cavity. However, the alternation of oral microbiota in NPC patients and its potential link to EBV reactivation and host cell response under the simultaneous existence of EBV and specific bacteria is largely unknown. Here, oral microbiota profiles of 303 NPC patients and controls with detailed clinical information, including serum EBV anti-virus capsid antigen (VCA) IgA level, were conducted. A distinct microbial community with lower diversity and imbalanced composition in NPC patients was observed. Notably, among enriched bacteria in patients, Streptococcus sanguinis was associated with anti-VCA IgA, an indicator of NPC risk and EBV reactivation. By measuring the concentration of its metabolite, hydrogen peroxide (H2O2), in the saliva of clinical patients, we found the detection rate of H2O2 was 2-fold increased compared to healthy controls. Further coculture assay of EBV-positive Akata cells with bacteria in vitro showed that S. sanguinis induced EBV lytic activation by its metabolite, H2O2. Host and EBV whole genome-wide transcriptome sequencing and EBV methylation assays showed that H2O2 triggered the host cell signaling pathways, notably tumor necrosis factor alpha (TNF-α) via NF-κB, and induced the demethylation of the global EBV genome and the expression of EBV lytic-associated genes, which could result in an increase of virus particle release and potential favorable events toward tumorigenesis. In brief, our study identified a characterized oral microbial profile in NPC patients and established a robust link between specific oral microbial alteration and switch of latency to lytic EBV infection status in the oral cavity, which provides novel insights into EBV's productive cycle and might help to further clarify the etiology of NPC. IMPORTANCE EBV is classified as the group I human carcinogen and is associated with multiple cancers, including NPC. The interplays between the microbiota and oncovirus in cancer development remain largely unknown. In this study, we investigate the interactions between resident microbes and EBV coexistence in the oral cavity of NPC patients. We identify a distinct oral microbial feature for NPC patients. Among NPC-enriched bacteria, we illustrated that a specific species, S. sanguinis, associated with elevated anti-IgA VCA in patients, induced EBV lytic activation by its by-product, H2O2, and activated the TNF-α/NF-κB pathway of EBV-positive B cells in vitro, together with increased detection rate of H2O2 in patients' oral cavities, which strengthened the evidence of bacteria-virus-host interaction in physiological circumstances. The effects of imbalanced microbiota on the EBV latent-to-lytic switch in the oral cavity might create the likelihood of EBV infection in epithelial cells at the nasopharynx and help malignant transition and cancer development.
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Affiliation(s)
- Ying Liao
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Jiang-Bo Zhang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Li-Xia Lu
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yi-Jing Jia
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Mei-Qi Zheng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Justine W. Debelius
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Yong-Qiao He
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Tong-Min Wang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Chang-Mi Deng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Xia-Ting Tong
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Wen-Qiong Xue
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Lian-Jing Cao
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Zi-Yi Wu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Da-Wei Yang
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Xiao-Hui Zheng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Xi-Zhao Li
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Yan-Xia Wu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Lin Feng
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jianbing Mu
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA
| | - Wei-Hua Jia
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- School of Public Health, Sun Yat-Sen University, Guangzhou, China
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21
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Su ZY, Siak PY, Leong CO, Cheah SC. The role of Epstein-Barr virus in nasopharyngeal carcinoma. Front Microbiol 2023; 14:1116143. [PMID: 36846758 PMCID: PMC9947861 DOI: 10.3389/fmicb.2023.1116143] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 01/27/2023] [Indexed: 02/11/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a metastasis-prone malignancy closely associated with the Epstein-Barr virus (EBV). Despite ubiquitous infection of EBV worldwide, NPC incidences displayed predominance in certain ethnic groups and endemic regions. The majority of NPC patients are diagnosed with advanced-stage disease, as a result of anatomical isolation and non-specific clinical manifestation. Over the decades, researchers have gained insights into the molecular mechanisms underlying NPC pathogenesis as a result of the interplay of EBV infection with several environmental and genetic factors. EBV-associated biomarkers were also used for mass population screening for the early detection of NPC. EBV and its encoded products also serve as potential targets for the development of therapeutic strategies and tumour-specific drug delivery. This review will discuss the pathogenic role of EBV in NPC and efforts in exploiting the potential of EBV-associated molecules as biomarkers and therapeutic targets. The current knowledge on the role of EBV and its associated products in NPC tumorigenesis, development and progression will offer a new outlook and potential intervention strategy against this EBV-associated malignancy.
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Affiliation(s)
- Zhi Yi Su
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, Negeri Sembilan, Malaysia
| | - Pui Yan Siak
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, Negeri Sembilan, Malaysia
| | - Chee-Onn Leong
- AGTC Genomics Sdn Bhd, Pusat Perdagangan Bandar, Persiaran Jalil 1, Bukit Jalil, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Shiau-Chuen Cheah
- Faculty of Medicine and Health Sciences, UCSI University, Bandar Springhill, Negeri Sembilan, Malaysia
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22
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Muacevic A, Adler JR, Sayed S, Siyal T, Das T. An Acute Presentation of Epstein-Barr Virus (EBV) Infection in an Immunocompromised Gentleman. Cureus 2022; 14:e33036. [PMID: 36721558 PMCID: PMC9881071 DOI: 10.7759/cureus.33036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/28/2022] [Indexed: 12/30/2022] Open
Abstract
Epstein-Barr virus (EBV) is a relevant cause of many clinical manifestations with a range of malignant and non-malignant presentations. This is particularly important to consider in immunosuppressed individuals. We present a case of a 36-year-old individual with ulcerative colitis who was in remission whilst taking mercaptopurine. The patient presented with weight loss, night sweats, and significant laboratory serum abnormalities on monitoring. Relevant investigations into his presentation ruled out a malignant feature, but his serology confirmed infection with EBV with the spread of infection to the liver and bone marrow. Overall, we identify a notable yet relevant clinical expression of EBV infection in the context of an immunosuppressed individual.
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23
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Yang Y, Yin L, Liu Q, Sun J, Adami HO, Ye W, Zhang Z, Fang F. Hospital-Treated Infections and Increased Risk of Two EBV-Related Malignancies: A Nested Case-Control Study. Cancers (Basel) 2022; 14:cancers14153804. [PMID: 35954467 PMCID: PMC9367337 DOI: 10.3390/cancers14153804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND To assess the association of hospital-treated infections with the subsequent risk of two Epstein-Barr virus (EBV)-related malignancies, namely Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC). METHODS We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with HL or NPC during 1994-2016 in Sweden, according to the Swedish Cancer Register. For each case, we randomly selected five controls individually matched to the case on sex and year of birth from the general Swedish population. Hospital-treated infections (i.e., infections requiring either inpatient or outpatient hospital care) were identified from the Swedish Patient Register. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HL and NPC, in relation to hospital-treated infections, after adjustment for age, sex, calendar period, educational achievement, and region of residence. RESULTS The study included a total of 890 cases of HL and 306 cases of NPC. A hospital-treated infection three years ago or earlier was associated with a higher risk of HL (OR = 1.49, 95%CI: 1.26-1.75) as well as NPC (OR = 1.36; 95%CI: 1.01-1.83). The positive association was noted for both bacterial and viral infections and primarily for respiratory and skin infections. A monotonous dose-response relationship was found between a number of hospital-treated infections and the risk of HL (p = 0.02) but less compelling for NPC (p = 0.06). Using a 5-year lag time rendered similar results (OR = 1.43, 95%CI: 1.21-1.70 for HL; OR = 1.43, 95%CI: 1.05-1.95 for NPC). CONCLUSIONS These findings suggest that infections requiring hospital treatment might contribute to the carcinogenesis of malignancies potentially related to EBV.
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Affiliation(s)
- Yanping Yang
- Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education/Guangxi Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Nanning 530021, China
| | - Li Yin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Qianwei Liu
- Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Jiangwei Sun
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Hans-Olov Adami
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden
- Clinical Effectiveness Group, Institute of Health and Society, University of Oslo, 0315 Oslo, Norway
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden
- Department of Epidemiology and Health Statistics & Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350005, China
| | - Zhe Zhang
- Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor (Guangxi Medical University), Ministry of Education/Guangxi Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Nanning 530021, China
- Correspondence: (Z.Z.); (F.F.); Tel.: +86-(0)-771-535-6511 (Z.Z.); +46-8-5248-6131 (F.F.)
| | - Fang Fang
- Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
- Correspondence: (Z.Z.); (F.F.); Tel.: +86-(0)-771-535-6511 (Z.Z.); +46-8-5248-6131 (F.F.)
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Huang Y, Liang J, Hu W, Liang Y, Xiao X, Zhao W, Zhong X, Yang Y, Pan X, Zhou X, Zhang Z, Cai Y. Integration Profiling Between Plasma Lipidomics, Epstein–Barr Virus and Clinical Phenomes in Nasopharyngeal Carcinoma Patients. Front Microbiol 2022; 13:919496. [PMID: 35847074 PMCID: PMC9281874 DOI: 10.3389/fmicb.2022.919496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/13/2022] [Indexed: 11/26/2022] Open
Abstract
Plasma lipidomics has been commonly used for biomarker discovery. Studies in cancer have suggested a significant alteration of circulating metabolite profiles which is correlated with cancer characteristics and treatment outcome. However, the lipidomics characteristics of nasopharyngeal carcinoma (NPC) have rarely been studied. We previously described the phenomenon of lipid droplet accumulation in NPC cells and showed that such accumulation could be regulated by latent infection of Epstein–Barr virus (EBV). Here, we compared the plasma lipidome of NPC patients to that of healthy controls by liquid chromatography-tandem mass spectrometry (LC–MS/MS). We found 19 lipids (e.g., phosphatidylinositols 18:0/20:4 and 18:0/18:2 and free fatty acid 22:6) to be remarkably decreased, whereas 2 lipids (i.e., diacylglycerols 16:0/16:1 and 16:0/20:3) to be increased, in the plasma of NPC patients, compared with controls. Different lipid profiles were also observed between patients with different titers of EBV antibodies (e.g., EA-IgA and VCA-IgA) as well as between patients with and without lymph node or distant organ metastasis. In conclusion, plasma lipidomics might help to differentiate NPC cases from controls, whereas EBV infection might influence the risk and prognosis of NPC through modulating lipid metabolism in both tumor cells and peripheral blood.
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Affiliation(s)
- Yi Huang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jinfeng Liang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wenjin Hu
- State Key Laboratory of Non-Food Biomass and Enzyme Technology, Guangxi Key Laboratory of Bio-refinery, National Engineering Research Center for Non-Food Biorefinery, Guangxi Biomass Engineering Technology Research Center, Guangxi Academy of Sciences, Nanning, China
| | - Yushan Liang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xue Xiao
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weilin Zhao
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xuemin Zhong
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
| | - Yanping Yang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
| | - Xinli Pan
- Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Beibu Gulf Marine Research Center, Guangxi Academy of Sciences, Nanning, China
| | - Xiaoying Zhou
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
| | - Zhe Zhang
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
- *Correspondence: Zhe Zhang,
| | - Yonglin Cai
- Guangxi Health Commission Key Laboratory of Molecular Epidemiology of Nasopharyngeal Carcinoma, Wuzhou Red Cross Hospital, Wuzhou, China
- Yonglin Cai,
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25
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Sinha S, Dickey BL, Coghill AE. Utility of Epstein-Barr virus (EBV) antibodies as screening markers for nasopharyngeal carcinoma: a narrative review. ANNALS OF NASOPHARYNX CANCER 2022; 6:6. [PMID: 35996401 PMCID: PMC9392954 DOI: 10.21037/anpc-21-12] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
BACKGROUND AND OBJECTIVE Nasopharyngeal carcinoma (NPC) is a tumor of the head and neck that arises from the mucosal epithelium of the nasopharynx. Epstein-Barr virus (EBV) is a human herpes virus and the necessary cause for NPC. The 5-year survival rate for NPC patients is higher when diagnosed at an earlier stage of disease. Therefore, NPC screening should be prioritized for early detection. The objective of this narrative review is to synthesize the existing literature from the past decade describing evaluations of EBV-based serological markers for NPC screening. METHODS We performed a literature search in PubMed for studies published from 2010 to 2020. Studies were required to be English-language articles. Twelve articles fulfilled all inclusion criteria, including eight studies conducted among the general population in southeastern China, three studies in genetically high-risk Taiwanese families, and one study comparing EBV serology versus circulating EBV DNA for NPC prediction. KEY CONTENT AND FINDINGS Studies suggest that EBV-based serology has the potential to be an effective tool to aid in early detection of NPC. The synthesized research also collectively suggests that incorporation of antibody against multiple EBV targets, as well as efforts to optimize assay output, can improve the ability of EBV serological markers to detect NPC. Finally, recent data from the only randomized trial provide preliminary evidence that screening using anti-EBV immunoglobulin A (IgA) antibody may achieve the goal of reducing mortality from NPC. CONCLUSIONS Late diagnosis is one of the reasons for poor survival after an NPC diagnosis. In high-risk areas, early diagnosis aided by EBV antibody could therefore improve survival.
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Affiliation(s)
- Sweta Sinha
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
- Center for Immunization and Infection Research in Cancer, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Brittney L. Dickey
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
- Center for Immunization and Infection Research in Cancer, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Anna E. Coghill
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
- Center for Immunization and Infection Research in Cancer, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
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Chen Y, Chang ET, Liu Q, Cai Y, Zhang Z, Chen G, Huang QH, Xie SH, Cao SM, Jia WH, Zheng Y, Li Y, Lin L, Ernberg I, Huang G, Zeng YX, Adami HO, Ye W. Environmental factors for Epstein-Barr virus reactivation in a high-risk area of nasopharyngeal carcinoma: a population-based study. Open Forum Infect Dis 2022; 9:ofac128. [PMID: 35450082 PMCID: PMC9017372 DOI: 10.1093/ofid/ofac128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/14/2022] [Indexed: 11/14/2022] Open
Abstract
Background Epstein-Barr virus (EBV) reactivation from latent to lytic infection has been considered as a key step in nasopharyngeal carcinoma oncogenesis. However, epidemiological evidence regarding environmental risk factors for EBV reactivation on a population level remains largely lacking. Methods We enrolled 1916 randomly selected adults from the general population of Guangdong and Guangxi, China, from 2010 to 2014. Information on environmental factors was collected via a structured interview. Serum immunoglobulin A antibodies against EBV viral capsid antigen and nuclear antigen 1 were measured by enzyme-linked immunosorbent assay to evaluate EBV reactivation status. We used logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the associations of EBV reactivation with various environmental factors. Results No associations were observed between EBV reactivation and extensive environmental factors, including alcohol or tea drinking, a history of chronic ear/nose/throat diseases, use of medications or herbs, consumption of salted fish or preserved foods, oral hygiene, sibship structure, and various residential and occupational exposures. Only cigarette smoking was associated with EBV reactivation (current smokers vs never smokers; OR = 1.37; 95% CI = 1.02–1.83), with positive exposure-response trends with increasing intensity, duration, and pack-years of smoking. Conclusions Consistent with previous studies, we found an association between cigarette smoking and EBV reactivation. Other examined exposures were not associated with EBV reactivation. These null results could suggest either more complex interactions between exposures and EBV reactivation or a predominant role of host and/or viral genetic variation.
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Affiliation(s)
- Yufeng Chen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Ellen T Chang
- Exponent, Inc., Center for Health Sciences, Menlo Park, CA, USA
| | - Qing Liu
- Department of Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine & Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Yonglin Cai
- Department of Clinical Laboratory, Wuzhou Red Cross Hospital, Wuzhou, China
- Wuzhou Health System Key Laboratory for Nasopharyngeal Carcinoma Etiology and Molecular Mechanism, Wuzhou, China
| | - Zhe Zhang
- Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Guomin Chen
- State Key Laboratory for Infectious Diseases Prevention and Control, Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | | | - Shang-Hang Xie
- Department of Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine & Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Su-Mei Cao
- Department of Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine & Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine & Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
| | - Yuming Zheng
- Department of Clinical Laboratory, Wuzhou Red Cross Hospital, Wuzhou, China
- Wuzhou Health System Key Laboratory for Nasopharyngeal Carcinoma Etiology and Molecular Mechanism, Wuzhou, China
| | - Yancheng Li
- Cangwu Institute for Nasopharyngeal Carcinoma Control and Prevention, Wuzhou, China
| | - Longde Lin
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Ingemar Ernberg
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Guangwu Huang
- Department of Otolaryngology-Head & Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, China
| | - Yi-Xin Zeng
- State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine & Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, China
- Beijing Hospital, Beijing, China
| | - Hans-Olov Adami
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Clinical Effectiveness Group, Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology and Health Statistics & Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
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Han S, Tay JK, Loh CJL, Chu AJM, Yeong JPS, Lim CM, Toh HC. Epstein–Barr Virus Epithelial Cancers—A Comprehensive Understanding to Drive Novel Therapies. Front Immunol 2021; 12:734293. [PMID: 34956172 PMCID: PMC8702733 DOI: 10.3389/fimmu.2021.734293] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/12/2021] [Indexed: 12/19/2022] Open
Abstract
Epstein–Barr virus (EBV) is a ubiquitous oncovirus associated with specific epithelial and lymphoid cancers. Among the epithelial cancers, nasopharyngeal carcinoma (NPC), lymphoepithelioma-like carcinoma (LELC), and EBV-associated gastric cancers (EBVaGC) are the most common. The role of EBV in the pathogenesis of NPC and in the modulation of its tumour immune microenvironment (TIME) has been increasingly well described. Much less is known about the pathogenesis and tumour–microenvironment interactions in other EBV-associated epithelial cancers. Despite the expression of EBV-related viral oncoproteins and a generally immune-inflamed cancer subtype, EBV-associated epithelial cancers have limited systemic therapeutic options beyond conventional chemotherapy. Immune checkpoint inhibitors are effective only in a minority of these patients and even less efficacious with molecular targeting drugs. Here, we examine the key similarities and differences of NPC, LELC, and EBVaGC and comprehensively describe the clinical, pathological, and molecular characteristics of these cancers. A deeper comparative understanding of these EBV-driven cancers can potentially uncover targets in the tumour, TIME, and stroma, which may guide future drug development and cast light on resistance to immunotherapy.
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Affiliation(s)
- Shuting Han
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Joshua K. Tay
- Department of Otolaryngology—Head & Neck Surgery, National University of Singapore, Singapore, Singapore
| | | | | | - Joe Poh Sheng Yeong
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Chwee Ming Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Han Chong Toh
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
- *Correspondence: Han Chong Toh,
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Frappier L. Epstein-Barr virus: Current questions and challenges. Tumour Virus Res 2021; 12:200218. [PMID: 34052467 PMCID: PMC8173096 DOI: 10.1016/j.tvr.2021.200218] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/14/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) infects most people worldwide and persists for life due to complicated interplay between lytic infection and multiple types of latent infections. While usually asymptomatic, EBV is a causative agent in several types of cancer and has a strong association with multiple sclerosis. Exactly how EBV promotes these diseases and why they are rare consequences of infection are incompletely understood. Here I will discuss current ideas on disease induction by EBV, including the importance of lytic protein expression in the context of latent infection as well as the possible importance of specific EBV variants in disease induction.
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Affiliation(s)
- Lori Frappier
- Department of Molecular Genetics, University of Toronto, 661 University Ave, Suite 1600, Toronto, ON, M5G 1M1, Canada.
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29
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Klufah F, Mobaraki G, Liu D, Alharbi RA, Kurz AK, Speel EJM, Winnepenninckx V, Zur Hausen A. Emerging role of human polyomaviruses 6 and 7 in human cancers. Infect Agent Cancer 2021; 16:35. [PMID: 34001216 PMCID: PMC8130262 DOI: 10.1186/s13027-021-00374-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Currently 12 human polyomaviruses (HPyVs) have been identified, 6 of which have been associated with human diseases, including cancer. The discovery of the Merkel cell polyomavirus and its role in the etiopathogenesis in the majority of Merkel cell carcinomas has drawn significant attention, also to other novel HPyVs. In 2010, HPyV6 and HPyV7 were identified in healthy skin swabs. Ever since it has been speculated that they might contribute to the etiopathogenesis of skin and non-cutaneous human cancers. MAIN BODY Here we comprehensively reviewed and summarized the current evidence potentially indicating an involvement of HPyV6 and HPyV7 in the etiopathogenesis of neoplastic human diseases. The seroprevalence of both HPyV6 and 7 is high in a normal population and increases with age. In skin cancer tissues, HPyV6- DNA was far more often prevalent than HPyV7 in contrast to cancers of other anatomic sites, in which HPyV7 DNA was more frequently detected. CONCLUSION It is remarkable to find that the detection rate of HPyV6-DNA in tissues of skin malignancies is higher than HPyV7-DNA and may indicate a role of HPyV6 in the etiopathogenesis of the respected skin cancers. However, the sheer presence of viral DNA is not enough to prove a role in the etiopathogenesis of these cancers.
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Affiliation(s)
- Faisal Klufah
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Ghalib Mobaraki
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Dan Liu
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Raed A Alharbi
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Anna Kordelia Kurz
- Department of Internal Medicine IV, RWTH Aachen University Hospital, Aachen, Germany
| | - Ernst Jan M Speel
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Véronique Winnepenninckx
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Axel Zur Hausen
- Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.
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Abstract
Glycoprotein B (gB) is an essential fusion protein for the Epstein-Barr virus (EBV) infection of both B cells and epithelial cells and is thus a promising target antigen for a prophylactic vaccine to prevent or reduce EBV-associated disease. T cell responses play key roles in the control of persistent EBV infection and in the efficacy of a vaccine. However, to date, T cell responses to gB have been characterized for only a limited number of human leukocyte antigen (HLA) alleles. Here, we screened gB T cell epitopes in 23 healthy EBV carriers and ten patients with nasopharyngeal cancer (NPC) using a peptide library spanning the entire gB sequence. We identified twelve novel epitopes in the context of seven new HLA restrictions that are common in Asian populations. Two epitopes, gB214-223 and gB840-849, restricted by HLA-B*58:01 and B*38:02, respectively, elicited specific CD8+ T cell responses to inhibit EBV-driven B cell transformation. Interestingly, gB-specific CD8+ T cells were more frequent in healthy viral carriers with EBV reactivation than in those without EBV reactivation, indicating that EBV reactivation in vivo stimulates both humoral (VCA-gp125-IgA) and cellular responses to gB. We further found that most gB epitopes are conserved among different EBV strains. Our study broadens the diversity and HLA restrictions of gB epitopes and suggests that gB is a common target of T cell responses in healthy viral carriers with EBV reactivation. In particular, the precisely mapped and conserved gB epitopes provide valuable information for prophylactic vaccine development.ImportanceT cells are crucial for the control of persistent EBV infection and the development of EBV-associated diseases. The EBV gB protein is essential for virus entry into B cells and epithelial cells and is thus a target antigen for vaccine development. Understanding T cell responses to gB is important for subunit vaccine design. Herein, we comprehensively characterized T cell responses to full-length gB. Our results expand the available gB epitopes and HLA restrictions, particularly those common in Asian populations. Furthermore, we showed that gB-specific CD8+ T cells inhibit B cell transformation ex vivo and that gB-specific CD8+ T cell responses in vivo may be associated with intermittent EBV reactivation in asymptomatic viral carriers. These gB epitopes are highly conserved among geographically separated EBV strains. Precisely mapped and conserved T cell epitopes may contribute to immune monitoring and to the development of a gB subunit vaccine.
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31
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Zhang WR, Du YY, Guo CY, Zhou HX, Lin JY, Meng XH, Mo HY, Luo DH. Prognostic Value of Serum Epstein-Barr Virus Antibodies and Their Correlation with TNM Classification in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma. Cancer Res Treat 2021; 53:991-1003. [PMID: 33494127 PMCID: PMC8524010 DOI: 10.4143/crt.2020.1298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 01/12/2021] [Indexed: 11/30/2022] Open
Abstract
Purpose This study assessed the correlation between Epstein-Barr virus (EBV) biomarkers and the eighth American Joint Committee on Cancer staging system and the prognostic values of IgG antibodies against replication and transcription activator (Rta-IgG), IgA antibodies against Epstein-Barr nuclear antigen 1, and BamH1 Z transactivator (Zta-IgA) in locoregionally advanced nasopharyngeal carcinoma (NPC) patients. Materials and Methods Serum EBV antibody levels were measured by enzyme-linked immunosorbent assay in 435 newly diagnosed stage III-IVA NPC patients administered intensity-modulated radiation therapy±chemotherapy. The primary endpoint was progression-free survival (PFS). Results Rta-IgG and Zta-IgA levels were positively correlated with the N category and clinical stage. Patients with high Rta-IgG levels (> 29.07 U/mL) showed a significantly inferior prognosis as indicated by PFS (77% vs. 89.8%, p=0.004), distant metastasis–free survival (DMFS) (88.3% vs. 95.8%, p=0.021), and local recurrence-free survival (LRFS) (91.2% vs. 98.3%, p=0.009). High Rta-IgG levels were also significantly associated with inferior PFS and LRFS in multivariable analyses. In the low-level EBV DNA group (≤ 1,500 copies/mL), patients with high Rta-IgG levels had significantly inferior PFS and DMFS (both p < 0.05). However, in the high-level EBV DNA group, Rta-IgG levels were not significantly associated with PFS, DMFS, and LRFS. In the advanced T category (T3–4) subgroup, high Rta-IgG levels were also significantly associated with inferior PFS, DMFS, and LRFS (both p < 0.05). Conclusion Rta-IgG and Zta-IgA levels were strongly correlated with the TNM classification. Rta-IgG level was a negative prognostic factor in locoregionally advanced NPC patients, especially those with advanced T category or low EBV DNA level.
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Affiliation(s)
- Wan-Ru Zhang
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yu-Yun Du
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chun-Yan Guo
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Han-Xing Zhou
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jie-Yi Lin
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiao-Han Meng
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Hao-Yuan Mo
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dong-Hua Luo
- Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, China
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Rao D, Fu M, Chen Y, Liu Q, Xiao L, Zhang X, Li Z, Li H, He Y, Chen Y, Chen J, Hu J, Huang Y. A combination of two ELISA tests for nasopharyngeal carcinoma screening in endemic areas based on a case-control study. PeerJ 2020; 8:e10254. [PMID: 33240616 PMCID: PMC7666820 DOI: 10.7717/peerj.10254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/06/2020] [Indexed: 11/20/2022] Open
Abstract
For populations with a high risk of nasopharyngeal carcinoma (NPC) in Guangdong province in southern China, mass screening is the first choice to prevent death from NPC. To improve the performance of NPC screening, we used a combination based on the IgA antibody against the Epstein-Barr virus (EBV) capsid antigen (VCA-IgA) and the IgA antibody against Epstein-Barr virus nuclear antigen 1 (EBNA1-IgA) to NPC screening by enzyme-linked immunosorbent assay (ELISA). A multiplication model was applied to measure the level of the combination. We evaluated the NPC screening effect of the markers.A case-control study was performed to assess the NPC screening effect of the markers. A total of 10,894 serum specimens were collected, including 554 samples from NPC patients and 10,340 samples from healthy controls. In the training stage, 640 subjects were randomly selected, including 320 NPC cases and 320 healthy controls. In the verification stage, 10,254 subjects were used to verify the NPC screening effect of the combination. Receiver operating characteristic (ROC) analysis was performed. In the verification stage, the combination achieved an sensitivity of 91.45%, a specificity of 93.45%, and an area under the ROC curve (AUC) of 0.978 (95% CI [0.968–0.987]). Compared with VCA-IgA and EBNA1-IgA individually, the combination had an improved screening performance. A probability (PROB) calculated by logistic regression model based on VCA-IgA and EBNA1-IgA was applied to NPC screening by ELISA in China. The AUC of the combination was a little bit larger than the PROB. There was a slight increase (3.13%) in the sensitivity of the combination compared to the sensitivity of the PROB, while the specificity was lower for the combination (92.50%) than for the PROB (95.94%). We successfully applied a combination of two ELISA tests based on VCA-IgA and EBNA1-IgA for NPC screening by using a multiplication model. The results suggested that the combination was effective and can be an option for NPC screening.
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Affiliation(s)
- Dongping Rao
- Department of Medical Records, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Meiqin Fu
- Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Yingjie Chen
- Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Qing Liu
- Department of Preventive Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Lin Xiao
- Department of Radiotherapy, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Xin Zhang
- Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Zhongxiao Li
- Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Haitao Li
- Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Yongyi He
- Department of Medical Records, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Yongxing Chen
- Department of Ear-Nose-Throat, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Jieying Chen
- Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Jin Hu
- Clinical Laboratory, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
| | - Yanming Huang
- Department of Respiratory Medicine, Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, Guangdong, China
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Morales-Sánchez A, Torres J, Cardenas-Mondragón MG, Romo-González C, Camorlinga-Ponce M, Flores-Luna L, Fuentes-Pananá EM. Detection of Epstein-Barr Virus DNA in Gastric Biopsies of Pediatric Patients with Dyspepsia. Pathogens 2020; 9:pathogens9080623. [PMID: 32751557 PMCID: PMC7459453 DOI: 10.3390/pathogens9080623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/25/2020] [Accepted: 07/27/2020] [Indexed: 12/21/2022] Open
Abstract
In this study, we assessed the presence of Epstein-Barr virus (EBV) in gastric samples derived from pediatric patients with dyspeptic symptoms, aiming to understand whether EBV participates in the development of early gastric lesions influencing chronic inflammation, in conjunction with the Helicobacter pylori (Hp) bacterium. We analyzed EBV load in 236 gastric biopsies derived from 186 pediatric patients with chronic dyspepsia and compared it with EBV serology, Hp load and serology, and with immune cell infiltration. We found that 7.5% of patients were positive for EBV load, ranging from 240 to 29,685 genomic copies/μg of DNA. Hp genomic sequences were found in 24.7% of patients. EBV positive samples did not correlate with Hp status and were characterized by absent to moderate immune cell infiltration. To our knowledge, this is the first study addressing EBV load in the stomach in a large cohort of pediatric patients with dyspeptic symptoms, providing evidence of EBV localization in the gastric mucosa in early inflammatory lesions. The lack of correlation between EBV and both Hp infection and inflammation is perhaps explained by independent pathogenic mechanisms or because of the randomness of the gastritis sampling. This is also supported by a moderate association between EBV load and serology.
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Affiliation(s)
- Abigail Morales-Sánchez
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gomez, Mexico City 06720, Mexico;
| | - Javier Torres
- Infectious Diseases Research Unit, CMNS-XXI, Mexican Institute of Social Security (IMSS), Mexico City 06720, Mexico; (J.T.); (M.G.C.-M.); (M.C.-P.)
| | - María G. Cardenas-Mondragón
- Infectious Diseases Research Unit, CMNS-XXI, Mexican Institute of Social Security (IMSS), Mexico City 06720, Mexico; (J.T.); (M.G.C.-M.); (M.C.-P.)
| | - Carolina Romo-González
- Laboratory of Experimental Bacteriology, National Institute of Pediatrics, Mexico City 04530, Mexico;
| | - Margarita Camorlinga-Ponce
- Infectious Diseases Research Unit, CMNS-XXI, Mexican Institute of Social Security (IMSS), Mexico City 06720, Mexico; (J.T.); (M.G.C.-M.); (M.C.-P.)
| | - Lourdes Flores-Luna
- Research Center in Population Health, National Institute of Public Health, Cuernavaca 62100, Mexico;
| | - Ezequiel M. Fuentes-Pananá
- Research Unit on Virology and Cancer, Children’s Hospital of Mexico Federico Gomez, Mexico City 06720, Mexico;
- Correspondence:
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Drosu NC, Edelman ER, Housman DE. Tenofovir prodrugs potently inhibit Epstein-Barr virus lytic DNA replication by targeting the viral DNA polymerase. Proc Natl Acad Sci U S A 2020; 117:12368-12374. [PMID: 32409608 PMCID: PMC7275665 DOI: 10.1073/pnas.2002392117] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes life-long infection and increases the risk for the development of several cancers and autoimmune diseases. The mechanisms by which chronic EBV infection leads to subsequent disease remain incompletely understood. Lytic reactivation plays a central role in the development of EBV-driven cancers and may contribute to other EBV-associated diseases. Thus, the clinical use of antivirals as suppressive therapy for EBV lytic reactivation may aid efforts aimed at disease prevention. Current antivirals for EBV have shown limited clinical utility due to low potency or high toxicity, leaving open the need for potent antivirals suitable for long-term prophylaxis. In the present study, we show that tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), drugs with excellent safety profiles used clinically for HIV prevention, inhibit EBV lytic DNA replication, with respective IC50 values of 0.30 μM and 84 nM. In a cell-based assay, TAF was 35- and 24-fold and TDF was 10- and 7-fold more potent than acyclovir and penciclovir, respectively, and TAF was also twice as potent as ganciclovir. The active metabolite of tenofovir prodrugs, tenofovir-diphosphate, inhibited the incorporation of dATP into a primed DNA template by the EBV DNA polymerase in vitro. In contrast to acyclovir, treatment of cells during latency for 24 h with TAF still inhibited EBV lytic DNA replication at 72 h after drug was removed. Our results suggest that tenofovir prodrugs may be particularly effective as inhibitors of EBV lytic reactivation, and that clinical studies to address critical questions about disease prevention are warranted.
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Affiliation(s)
- Natalia C Drosu
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139;
- Health Sciences & Technology, Harvard Medical School, Boston, MA 02115
| | - Elazer R Edelman
- Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139
- Health Sciences & Technology, Harvard Medical School, Boston, MA 02115
- Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115
| | - David E Housman
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
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Chen H, Zhong Q, Wu X, Ding Y, Chen Q, Xue N, Xu Y, Chen S. Preliminary evaluation of a candidate international reference for Epstein-Barr virus capsid antigen immunoglobulin A in China. Infect Agent Cancer 2020; 15:25. [PMID: 32368250 PMCID: PMC7191735 DOI: 10.1186/s13027-020-00294-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/24/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The detection of the Epstein-Barr capsid antigen (VCA) immunoglobulin A (IgA) is widely used in the diagnosis of nasopharyngeal carcinoma (NPC), but a reference standard for evaluating the presence of VCA-IgA is not yet available. Therefore, a reference standard is urgently needed for a uniform and quantitative detection of VCA-IgA. METHODS A mixed reference serum from three NPC patients diluted with healthy subject serum was made as a potential first international standard for VCA-IgA. VCA-IgA was detected in twenty NPC patients by four ELISA kits and two chemiluminescent immunoassays kits using the reference as a calibration curve. The performance of these six kits was evaluated, and the quantitative results were compared. RESULTS Our results showed a good linearity of the reference in different kits. Without reference, the difference of the total coefficient of variation (from 3.98 to 43.11%) and Within-run coefficient of variation (from 2.47 to 19.66%) was large in the 6 kits. The positive and negative coincidence rate between the 6 kits and indirect immunofluorescence for NPC diagnosis was 75% overall agreement, but a difference among the six kits was found, ranging from 55 to 90%. The concentration of VCA-IgA in the 20 NPC samples led in the division into three categories such as negative, low, or medium/high positive, but these concentrations were significantly different within these three categories depending on the kit used of the 6 considered. However,a good correlation (R2 = 0.986) was observed between Antu and Beier ELISA kits. CONCLUSIONS The reference serum mightbe used as a reference standard for a better comparison of the results from different kits/laboratories. However, the quantitative results of some kits are still inconsistent due to the diversity of VCA antigens.
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Affiliation(s)
- Hao Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060 People’s Republic of China
| | - Qiaohua Zhong
- Department of Clinical Laboratory ,People’s Hospital of Jieyang, Jieyang Hospital Affiliated to SunYat-sen University, Tianfu Road 107, Rongcheng District, Jieyang City, 522000 Guangdong Province People’s Republic of China
| | - Xiaobin Wu
- Department of Laboratory Science, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, People’s Republic of China
| | - Yanling Ding
- Department of Clinical Laboratory, Liuzhou Maternity and Child Health Care Hospital, Yingshan Road 50th, Chengzhong District, Liuzhou, 545001 People’s Republic of China
| | - Qi Chen
- Department of Clinical Laboratory ,People’s Hospital of Jieyang, Jieyang Hospital Affiliated to SunYat-sen University, Tianfu Road 107, Rongcheng District, Jieyang City, 522000 Guangdong Province People’s Republic of China
| | - Ning Xue
- Department of Clinical Laboratory, Affiliated Tumor Hospital of Zhengzhou University, Henan Tumor Hospital, Zhengzhou, 450100 People’s Republic of China
| | - Yiwei Xu
- Department of clinical laboratory, The cancer hospital of Shantou University Medical college, The Key laboratory of Molecular Biology for high cancer incidence coastal Chaoshan area, Shantou University Medical college, number 22, Xinling road, Shantou, Guangdong 515041 People’s Republic of China
| | - Shulin Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, 510060 People’s Republic of China
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Validation of an Epstein-Barr Virus Antibody Risk Stratification Signature for Nasopharyngeal Carcinoma by Use of Multiplex Serology. J Clin Microbiol 2020; 58:JCM.00077-20. [PMID: 32102852 DOI: 10.1128/jcm.00077-20] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 02/19/2020] [Indexed: 12/26/2022] Open
Abstract
Serological testing for nasopharyngeal carcinoma (NPC) has recently been reinvigorated by the implementation of novel Epstein-Barr virus (EBV)-specific IgA and IgG antibodies from a proteome array. Although proteome arrays are well suited for comprehensive antigen selection, they are not applicable for large-scale studies. We adapted a 13-marker EBV antigen signature for NPC risk identified by proteome arrays to multiplex serology to establish an assay for large-scale studies. Taiwanese NPC cases (n = 175) and matched controls (n = 175) were used for assay validation. Spearman's correlation was calculated, and the diagnostic value of all multiplex markers was assessed independently using the area under the receiver operating characteristic curve (AUC). Two refined signatures were identified using stepwise logistic regression and internally validated with 10-fold cross validation. Array and multiplex serology showed strong correlation for each individual EBV marker, as well as for a 13-marker combined model on continuous data. Two refined signatures with either four (LF2 and BGLF2 IgG, LF2 and BMRF1 IgA) or two (LF2 and BGLF2 IgG) antibodies on dichotomous data were identified as the most parsimonious set of serological markers able to distinguish NPC cases from controls with AUCs of 0.992 (95% confidence interval [CI], 0.983 to 1.000) and 0.984 (95% CI, 0.971 to 0.997), respectively. Neither differed significantly from the 13-marker model (AUC, 0.992; 95% CI, 0.982 to 1.000). All models were internally validated. Multiplex serology successfully validated the original EBV proteome microarray data. Two refined signatures of four and two antibodies were capable of detecting NPC with 99.2% and 98.4% accuracy.
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37
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Camargo MC, Kim KM, Matsuo K, Torres J, Liao LM, Morgan D, Michel A, Waterboer T, Song M, Gulley ML, Dominguez RL, Yatabe Y, Kim S, Cortes-Martinez G, Lissowska J, Zabaleta J, Pawlita M, Rabkin CS. Circulating Antibodies against Epstein-Barr Virus (EBV) and p53 in EBV-Positive and -Negative Gastric Cancer. Cancer Epidemiol Biomarkers Prev 2020; 29:414-419. [PMID: 31719065 PMCID: PMC8272980 DOI: 10.1158/1055-9965.epi-19-0790] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 10/01/2019] [Accepted: 11/04/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serologic profiles may inform viral contribution to carcinogenesis. METHODS We compared humoral responses of EBV-positive (n = 67) and EBV-negative (n = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer. RESULTS Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, P < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, P = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, P = 0.021). Anti-p53 prevalence from the literature was 15%. CONCLUSIONS These serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype. IMPACT Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies.
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Affiliation(s)
- M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
| | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Japan
| | - Javier Torres
- Unidad de Investigación en Enfermedades Infecciosas, UMAE Pediatría, CMN SXXI, Instituto Mexicano del Seguro Social, México City, México
| | - Linda M Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Douglas Morgan
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama
| | - Angelika Michel
- Infections and Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Minkyo Song
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | - Ricardo L Dominguez
- Department of Medicine, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Yasushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Sung Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gustavo Cortes-Martinez
- Servicio de Cirugía, Hospital de Oncología, CMN SXXI, Instituto Mexicano del Seguro Social, México City, México
| | - Jolanta Lissowska
- Division of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Jovanny Zabaleta
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Michael Pawlita
- Infections and Cancer Epidemiology, German Cancer Research Center (DFKZ), Heidelberg, Germany
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
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Liu Z, Yu KJ, Coghill AE, Brenner N, Cao SM, Chen CJ, Chen Y, Doolan DL, Hsu WL, Labo N, Middeldorp JM, Miley W, Simon J, Wang CP, Waterboer T, Whitby D, Xie SH, Ye W, Hildesheim A. Multilaboratory Assessment of Epstein-Barr Virus Serologic Assays: the Case for Standardization. J Clin Microbiol 2019; 57:e01107-19. [PMID: 31434722 PMCID: PMC6813000 DOI: 10.1128/jcm.01107-19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 08/14/2019] [Indexed: 12/13/2022] Open
Abstract
IgA antibodies targeting Epstein-Barr virus (EBV) have been proposed for screening for nasopharyngeal carcinoma (NPC). However, methods differ, and the antigens used in these assays differ considerably between laboratories. To enable formal comparisons across a range of established EBV serology assays, we created a panel of 66 pooled serum samples and 66 pooled plasma samples generated from individuals with a broad range of IgA antibody levels. Aliquots from these panels were distributed to six laboratories and were tested by 26 assays measuring antibodies against VCA, EBNA1, EA-EBNA1, Zta, or EAd antigens. We estimated the correlation between assay pairs using Spearman coefficients (continuous measures) and percentages of agreement (positive versus negative, using predefined positivity cutoffs by each assay developer/manufacturer). While strong correlations were observed between some assays, considerable differences were also noted, even for assays that targeted the same protein. For VCA-IgA assays in serum, two distinct clusters were identified, with a median Spearman coefficient of 0.41 (range, 0.20 to 0.66) across these two clusters. EBNA1-IgA assays in serum grouped into a single cluster with a median Spearman coefficient of 0.79 (range, 0.71 to 0.89). Percentages of agreement differed broadly for both VCA-IgA (12% to 98%) and EBNA1-IgA (29% to 95%) assays in serum. Moderate-to-strong correlations were observed across assays in serum that targeted other proteins (correlations ranged from 0.44 to 0.76). Similar results were noted for plasma. We conclude that standardization of EBV serology assays is needed to allow for comparability of results obtained in different translational research studies across laboratories and populations.
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Affiliation(s)
- Zhiwei Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Kelly J Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Anna E Coghill
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
- Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
| | - Nicole Brenner
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Su-Mei Cao
- Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Yufeng Chen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Denise L Doolan
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
| | - Wan-Lun Hsu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Nazzarena Labo
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos-Biomedical, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Jaap M Middeldorp
- Department of Pathology, VU University Medical Center, Amsterdam, Netherlands
| | - Wendell Miley
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos-Biomedical, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Julia Simon
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Cheng-Ping Wang
- Department of Otolaryngology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Denise Whitby
- Viral Oncology Section, AIDS and Cancer Virus Program, Leidos-Biomedical, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Shang-Hang Xie
- Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Allan Hildesheim
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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Ji MF, Sheng W, Cheng WM, Ng MH, Wu BH, Yu X, Wei KR, Li FG, Lian SF, Wang PP, Quan W, Deng L, Li XH, Liu XD, Xie YL, Huang SJ, Ge SX, Huang SL, Liang XJ, He SM, Huang HW, Xia SL, Ng PS, Chen HL, Xie SH, Liu Q, Hong MH, Ma J, Yuan Y, Xia NS, Zhang J, Cao SM. Incidence and mortality of nasopharyngeal carcinoma: interim analysis of a cluster randomized controlled screening trial (PRO-NPC-001) in southern China. Ann Oncol 2019; 30:1630-1637. [PMID: 31373615 DOI: 10.1093/annonc/mdz231] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Previous mass screening studies have shown that IgA antibodies against Epstein-Barr Virus (EBV) can facilitate early detection of nasopharyngeal carcinoma (NPC), but the impact of EBV-antibody screening for NPC-specific mortality remains unknown. PATIENTS AND METHODS A prospective, cluster randomized, controlled trial for NPC screening (PRO-NPC-001) was conducted in 3 selected towns of Zhongshan City and 13 selected towns of Sihui City in southern China beginning in 2008. Serum samples of the screening group were tested for two previously selected anti-EBV antibodies. Subjects with serological medium risk were subsequently retested annually for 3 years, and those with serological high risk were referred to otorhinolaryngologists for diagnostic check-up. An interim analysis was carried out to evaluate the primary end points of the NPC-specific mortality and the early diagnostic rate, and the secondary end point of the NPC incidence, through linkage with the database of Zhongshan City. RESULTS Among 70 296 total subjects, 29 413 screened participants (41.8% of the total subjects) in the screening group and 50 636 in the control group, 153 (43.3 per 100 000 person-year), 62 (55.3 per 100 000 person-year) and 99 (33.1 per 100 000 person-year) NPC cases were identified. The early diagnostic rates of NPC were significantly higher in the participants (79.0%, P < 0.0001) and the screening group (45.9%, P < 0.0001) compared with the control group (20.6%). Although no differences were found between NPC-specific mortality of the screening group and the control group [relative risk (RR)= 0.82, 95% confidence interval (CI) 0.37-1.79], lower NPC-specific mortality was noticed among participants from the screening group versus the control group (RR = 0.22, 95% CI 0.09-0.49). CONCLUSION IgA antibodies against EBV can identify high-risk population and was effective in screening for early asymptomatic NPC. Although the mortality reduction was not significant in the primary end point, we noted encouraging evidence of a mortality reduction in screening participants in this interim analysis. CLINICAL TRIAL NUMBER NCT00941538.
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Affiliation(s)
- M F Ji
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - W Sheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biological Products, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - W M Cheng
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - M H Ng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biological Products, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - B H Wu
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - X Yu
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - K R Wei
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - F G Li
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - S F Lian
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - P P Wang
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - W Quan
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - L Deng
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - X H Li
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - X D Liu
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - Y L Xie
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - S J Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biological Products, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - S X Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biological Products, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - S L Huang
- Xiaolan Public Health Service Center, Zhongshan, People's Republic of China
| | - X J Liang
- Xiaolan Public Health Service Center, Zhongshan, People's Republic of China
| | - S M He
- Xiaolan People's Hospital of Zhongshan City, Zhongshan, People's Republic of China
| | - H W Huang
- Chen Xinhai Hospital of Xiaolan, Zhongshan, People's Republic of China
| | - S L Xia
- Zhongshan Center for Disease Control and Prevention, Zhongshan, People's Republic of China
| | - P S Ng
- State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology and Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, SAR
| | - H L Chen
- State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology and Research Centre of Infection and Immunology, The University of Hong Kong, Hong Kong, SAR
| | - S H Xie
- State Key Laboratory of Oncology in Southern China, Department of Epidemiology, Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Q Liu
- State Key Laboratory of Oncology in Southern China, Department of Epidemiology, Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - M H Hong
- State Key Laboratory of Oncology in Southern China, Department of Epidemiology, Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - J Ma
- State Key Laboratory of Oncology in Southern China, Department of Epidemiology, Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Y Yuan
- Cancer Research Institute of Zhongshan City, Zhongshan Hospital of Sun Yat-sen University, Zhongshan, People's Republic of China
| | - N S Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biological Products, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - J Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biological Products, School of Public Health, Xiamen University, Xiamen, People's Republic of China.
| | - S M Cao
- State Key Laboratory of Oncology in Southern China, Department of Epidemiology, Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
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Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation. J Virol 2019; 93:JVI.00989-19. [PMID: 31341047 DOI: 10.1128/jvi.00989-19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 07/17/2019] [Indexed: 12/20/2022] Open
Abstract
Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication. Lytic reactivation starts with derepression of the Zp promoter controlling BZLF1 gene expression, which binds and is activated by the c-Jun transcriptional activator. Here, we identified the cellular Arkadia-like 1 (ARKL1) protein as a negative regulator of Zp and EBV reactivation. Silencing of ARKL1 in the context of EBV-positive gastric carcinoma (AGS) cells, nasopharyngeal carcinoma (NPC43) cells, and B (M81) cells led to increased lytic protein expression, whereas overexpression inhibited BZLF1 expression. Similar effects of ARKL1 modulation were seen on BZLF1 transcripts as well as on Zp activity in Zp reporter assays, showing that ARKL1 repressed Zp. Proteomic profiling of ARKL1-host interactions identified c-Jun as an ARKL1 interactor, and reporter assays for Jun transcriptional activity showed that ARKL1 inhibited Jun activity. The ARKL1-Jun interaction required ARKL1 sequences that we previously showed mediated binding to the CK2 kinase regulatory subunit CK2β, suggesting that CK2β might mediate the ARKL1-Jun interaction. This model was supported by the findings that silencing of CK2β, but not the CK2α catalytic subunit, abrogated the ARKL1-Jun interaction and phenocopied ARKL1 silencing in promoting EBV reactivation. Additionally, ARKL1 was associated with Zp in reporter assays and this was increased by additional CK2β. Together, the data indicate that ARKL1 is a negative regulator of Zp and EBV reactivation that acts by inhibiting Jun activity through a CK2β-mediated interaction.IMPORTANCE Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication and is associated with several types of cancer. We have identified a cellular protein (ARKL1) that acts to repress the reactivation of EBV from the latent to the lytic cycle. We show that ARKL1 acts to repress transcription of the EBV lytic switch protein by inhibiting the activity of the cellular transcription factor c-Jun. This not only provides a new mechanism of regulating EBV reactivation but also identifies a novel cellular function of ARKL1 as an inhibitor of Jun-mediated transcription.
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Guo X, Li T, Li F, Xu Y, Wang H, Cheng W, Tang J, Zhou G, Chen H, Ng M, Ji M, Ge S, Xia N. Intermittent abortive reactivation of Epstein-Barr virus during the progression of nasopharyngeal cancer as indicated by elevated antibody levels. Oral Oncol 2019; 93:85-90. [PMID: 31109701 DOI: 10.1016/j.oraloncology.2019.04.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/15/2019] [Accepted: 04/27/2019] [Indexed: 12/12/2022]
Abstract
The development of nasopharyngeal carcinoma (NPC), a common cancer in Southeastern Asia, is closely associated with Epstein-Barr virus (EBV) infection; however, the aetiological role of EBV in NPC pathogenesis remains enigmatic. The life cycle of EBV in NPC patients is defined as latency II, while the antibodies specific to lytic phase proteins, as well as lytic genes, were highly expressed in NPC patients. The correlation between antibody levels and the progression of NPC has been reported in some studies; however, most of these studies focused on IgA antibodies, and the results in different articles were not consistent. In this study, we concurrently determined the levels of IgA and IgG antibodies specific to six purified recombinant EBV antigens associated with different replication statuses of EBV: EBNA1 associated with latency II; the non-structural antigens Zta, TK, EA-D and EA-R associated with immediate-early and early lytic phases; and the EBV matrix protein VCA p18, which is involved in late lytic phase. Levels of antibodies specific to immediate-early and early antigens were correlated with the tumour progression, especially tumour size. The levels of antibodies specific to some lytic phase antigens were also correlated with lymph node inclusion and metastasis. However, the antibody specific to the latency II antigen EBNA1 was not correlated with either tumour size or metastasis. Consistent with previous transcriptome studies, the results suggested both the expression of lytic phase genes at the protein level and the intermittent reactivation of EBV in NPC patients.
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Affiliation(s)
- Xiaoyi Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Tingdong Li
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan, Guangdong 528403, PR China
| | - Yarui Xu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Han Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Weimin Cheng
- Cancer Research Institute of Zhongshan City, Zhongshan, Guangdong 528403, PR China
| | - Jiabao Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Guoliang Zhou
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Honglin Chen
- State Key Laboratory for Emerging Infectious Diseases, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Munhon Ng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan, Guangdong 528403, PR China.
| | - Shengxiang Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China.
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science and School of Public Health, Xiamen University, Xiamen 361102, Fujian, PR China
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Hu T, Lin CY, Xie SH, Chen GH, Lu YQ, Ling W, Huang QH, Liu Q, Cao SM. Smoking can increase nasopharyngeal carcinoma risk by repeatedly reactivating Epstein-Barr Virus: An analysis of a prospective study in southern China. Cancer Med 2019; 8:2561-2571. [PMID: 30843658 PMCID: PMC6536979 DOI: 10.1002/cam4.2083] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/17/2019] [Accepted: 02/18/2019] [Indexed: 02/06/2023] Open
Abstract
Background The association between smoking and nasopharyngeal carcinoma (NPC) is still uncertain. The aim of this study was to validate smoking effect on NPC and explore if smoking can induce NPC by persistently reactivating EBV in long‐term based on a prospective cohort design. Methods A NPC screening cohort with 10 181 eligible residents in Sihui city, southern China was conducted from 2008 to 2015. The smoking habit was investigated through the trained interviewers and EBV antibodies (VCA‐IgA, EBNA1‐IgA) as screening markers were tested periodically. New NPC cases were identified through local cancer registry. Cox's regression model was used to estimate the adjusted hazard ratios (aHRs) of smoking on NPC incidence. In the non‐NPC participants, the associations between smoking and EBV seropositivity in different periods were assessed by logistic regression and generalized estimating equations (GEE). Results With a median of 7.54 years, 71 NPCs were diagnosed ≥1 year after recruitment. Compared with never smokers, the aHRs of developing NPC among ever smokers were 3.00 (95%CI: 1.46‐6.16). Stratified by sex, the HRs of ever smoking were 2.59 (95%CI: 1.07‐6.23) for male and 3.75 (95%CI: 1.25‐11.20) for female, respectively. Among the non‐NPC individuals, ever smoking was not only associated with EBV seropositivity at baseline, but also in the 3‐5 years of follow up, with adjusted odds ratios (aORs) of 1.68 (95%CI: 1.29‐2.18) for VCA‐IgA and 1.92 (95%CI: 1.42‐2.59) for EBNA1‐IgA. Among the smokers who were tested EBV antibodies at least twice, the similar results were obtained using GEE. Conclusion Smoking could significantly increase the long‐term risk of NPC in southern China, partly by persistently reactivating EBV.
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Affiliation(s)
- Ting Hu
- Department of Cancer Prevention, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Chu-Yang Lin
- Department of Cancer Prevention, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Shang-Hang Xie
- Department of Cancer Prevention, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Geng-Hang Chen
- Department of Cancer Prevention, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.,School of Public Health, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yu-Qiang Lu
- Sihui Cancer Institute, Sihui, People's Republic of China
| | - Wei Ling
- Sihui Cancer Institute, Sihui, People's Republic of China
| | - Qi-Hong Huang
- Sihui Cancer Institute, Sihui, People's Republic of China
| | - Qing Liu
- Department of Cancer Prevention, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Su-Mei Cao
- Department of Cancer Prevention, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
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Chen H, Ji M, Zong JF, Ko JMY, Dai W, Lung ML. Conventional and Novel Diagnostic Biomarkers and Approaches for Detection of Nasopharyngeal Carcinoma. NASOPHARYNGEAL CARCINOMA 2019:129-153. [DOI: 10.1016/b978-0-12-814936-2.00007-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Jiang C, Chen J, Xie S, Zhang L, Xiang Y, Lung M, Kam NW, Kwong DLW, Cao S, Guan XY. Evaluation of circulating EBV microRNA BART2-5p in facilitating early detection and screening of nasopharyngeal carcinoma. Int J Cancer 2018; 143:3209-3217. [PMID: 29971780 DOI: 10.1002/ijc.31642] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/19/2018] [Accepted: 04/17/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Chen Jiang
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Jinna Chen
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Shanghang Xie
- Department of Epidemiology, Cancer Prevention Center; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Lifang Zhang
- Department of Epidemiology, Cancer Prevention Center; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Yanqun Xiang
- Department of Nasopharyngeal Carcinoma; Sun Yat-Sen University Cancer Center; Guangzhou China
| | - Maria Lung
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Ngar-Woon Kam
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Dora Lai-wan Kwong
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
| | - Sumei Cao
- Department of Epidemiology, Cancer Prevention Center; State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center; Guangzhou China
| | - Xin-Yuan Guan
- Department of Clinical Oncology; The University of Hong Kong; Pokfulam, Hong Kong
- State Key Laboratory of Oncology in Southern China; Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center; Guangzhou China
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Varga MG, Cai H, Waterboer T, Murphy G, Shimazu T, Taylor PR, Qiao YL, Park SK, Yoo KY, Jee SH, Cho ER, Kim J, Abnet CC, Tsugane S, Cai Q, Zheng W, Pawlita M, Shu XO, Epplein M. Epstein-Barr Virus Antibody Titers Are Not Associated with Gastric Cancer Risk in East Asia. Dig Dis Sci 2018; 63:2765-2772. [PMID: 29948559 PMCID: PMC6139270 DOI: 10.1007/s10620-018-5154-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 05/30/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV)-positive gastric cancers represent a distinct subtype of gastric cancers and account for nearly 10% of the gastric cancer burden, yet risk detection strategies for this cancer subtype are lacking. METHODS We conducted a nested case-control study where we assayed 4 EBV antigens [viral capsid antigen (VCA), early antigen (EA), Epstein-Barr nuclear antigen (EBNA), and BZLF1-encoded replication activator protein (ZEBRA)] in either sera or plasma from 1447 gastric cancer cases and 1797 controls obtained from seven prospective cohorts representing individuals from the high gastric cancer-risk countries of China, Japan, and Korea. RESULTS The prevalence of EBV sero-positivity was universal with the exception of one sero-negative individual, and the highest titers of the EBV antigens VCA (OR 0.95, 95% CI 0.78-1.17), EBNA (OR 0.88, 95% CI 0.72-1.08), EA (OR 0.97, 95% CI 0.79-1.19), and ZEBRA (OR 0.87, 95% CI 0.71-1.07) were not associated with risk of incident gastric cancer. When we stratified these data by H. pylori status, there was no change in the association. CONCLUSIONS Multiplex serology of the aforementioned EBV antigens in serum may not be a suitable biomarker for predicting gastric cancer risk in East Asian populations.
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Affiliation(s)
- Matthew G. Varga
- Department of Epidemiology, Gillings School of Global Public Health
and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel
Hill, 3207B Michael Hooker Research Center, Chapel Hill, NC 27599, USA,Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Hui Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Tim Waterboer
- Division of Molecular Diagnostics of Oncogenic Infections, Research
Program in Infection, Inflammation, and Cancer, German Cancer Research Center
(DFKZ), 69120 Heidelberg, Germany
| | - Gwen Murphy
- Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, MD 20892, USA
| | - Taichi Shimazu
- Epidemiology and Prevention Group, National Cancer Center, Tokyo
104-0045, Japan
| | - Phil R. Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, MD 20892, USA
| | - You-Lin Qiao
- Department of Cancer Epidemiology, Chinese Academy of Medical
Sciences and Peking Union Medial College, Beijing 100021, China
| | - Sue K. Park
- Department of Biomedical Sciences, Cancer Research Institute, Seoul
National University College of Medicine, Seoul 110-799, Korea
| | - Keun-Young Yoo
- Department of Preventive Medicine, Seoul National University College
of Medicine, Seoul 110-799, Korea
| | - Sun Ha Jee
- Department of Epidemiology and Health Promotion, Institute for
Health Promotion, Yonsei University, Seoul 120-752, Korea
| | - Eo Rin Cho
- Department of Epidemiology and Health Promotion, Institute for
Health Promotion, Yonsei University, Seoul 120-752, Korea
| | - Jeongseon Kim
- Division of Cancer Epidemiology and Prevention, Research Institute,
National Cancer Center, Goyang 410-769, Korea
| | - Christian C. Abnet
- Division of Cancer Epidemiology and Genetics, National Cancer
Institute, Bethesda, MD 20892, USA
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, National Cancer Center, Tokyo
104-0045, Japan
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Research
Program in Infection, Inflammation, and Cancer, German Cancer Research Center
(DFKZ), 69120 Heidelberg, Germany
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA
| | - Meira Epplein
- Division of Epidemiology, Department of Medicine, Vanderbilt
Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center,
Nashville, TN 37203, USA,Department of Population Health Sciences, Duke University and
Cancer Control and Population Sciences Program, Duke Cancer Institute, Durham, NC
27705, USA
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Gallardo F, Mariamé B, Gence R, Tilkin-Mariamé AF. Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:2805-2814. [PMID: 30233143 PMCID: PMC6135081 DOI: 10.2147/dddt.s172538] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Purpose The Epstein-Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasopharynx, surgery is rarely used to treat primary NPC cancers. Treatment by radiotherapy, combined or not with chemotherapy, are efficient for primary tumors but often do not protect against fatal relapses or metastases. Methods Search for new therapeutic molecules through high content screening lead to the identification of Ivermectin (IVM) as a promising drug. IVM is a US Food and Drug Administration-approved macrocyclic lactone widely used as anthelmintic and insecticidal agent that has also shown protective effects against cancers. Results We show here that IVM has cytotoxic activity in vitro against NPC cells, in which it reduces MAPKs pathway activation through the inhibition PAK-1 activity. Moreover, all macrocyclic lactones tested and a PAK1 inhibitor are cytotoxic in vitro for EBV-positive and EBV-negative NPC tumor cells. We have also shown that IVM intraperitoneal repeated injections, at US Food and Drug Administration-approved doses, have no significant toxicity and decrease NPC subcutaneous tumors development in nude mice. Conclusion Macrocyclic lactones appear as promising molecules against NPC targeting PAK-1 with no detectable adverse effect.
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Affiliation(s)
- Franck Gallardo
- NeoVirTech, SAS, Institut for Advanced Technology in Life Science (ITAV), Toulouse, France,
| | | | - Remi Gence
- INSERM UMR 1037, CRCT, University of Toulouse, Toulouse, France
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Cai Y, Song Y, Cen D, Zhang C, Mao S, Ye X, Xiong Y, Jiang P, Chen J, Xue X, Zhang L, Zhu G. Novel ELISA for serodiagnosis of nasopharyngeal carcinoma based on a B cell epitope of Epstein-Barr virus latent membrane protein 2. Oncol Lett 2018; 16:4372-4378. [PMID: 30214572 PMCID: PMC6126329 DOI: 10.3892/ol.2018.9216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Accepted: 09/07/2017] [Indexed: 12/18/2022] Open
Abstract
Epstein-Barr virus (EBV) is widespread and is associated with nasopharyngeal carcinoma (NPC). Serological detection of EBV is commonly used for screening, diagnosis and epidemiological surveys of NPC. In the present study, a novel B cell multi-epitope peptide fusion protein (EBV-LMP2-3B), which is composed of three B cell linear epitopes (RIEDPPFNSLL, TLNLT and KSLSSTEFIPN) of EBV latent membrane protein 2 (LMP2), was expressed in a prokaryotic expression system and purified using Ni2+-nitrilotriacetate-Sepharose. The immunogenicity and binding specificity of EBV-LMP2-3B were evaluated on the basis of antibody responses in immunized BALB/c mice, western blotting and indirect immunofluorescence assay. Evaluation of EBV-LMP2-3B as a serological diagnostic reagent was performed using an indirect ELISA in 198 patients with NPC and 102 healthy adults. These results revealed that EBV-LMP2-3B was able to eliminate the high-titer serum antibody response in BALB/c mice. Western blot analysis and indirect immunofluorescence assay confirmed that the mouse immune sera recognized the native LMP2. Compared with healthy adults, patients with NPC demonstrated significantly greater reactivity to EBV-LMP2-3B (P<0.05). Furthermore, it was possible to effectively detect specific IgG in sera from patients with NPC, with a sensitivity of 91.91% and specificity of 93.14%, representing an improvement over the traditional viral capsid antigen-IgA-based detection method with 59.59% sensitivity and 75.49% specificity. In conclusion, the EBV-LMP2-3B protein may be used as a serological diagnostic reagent to screen for and diagnose NPC.
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Affiliation(s)
- Yiqi Cai
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yiling Song
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Danwei Cen
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Chanqiong Zhang
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Shanshan Mao
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaoxian Ye
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Yirong Xiong
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Pengfei Jiang
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jun Chen
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiangyang Xue
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Lifang Zhang
- Institute of Molecular Virology and Immunology, Department of Medical Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Guanbao Zhu
- Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Guidry JT, Birdwell CE, Scott RS. Epstein-Barr virus in the pathogenesis of oral cancers. Oral Dis 2018; 24:497-508. [PMID: 28190296 PMCID: PMC5554094 DOI: 10.1111/odi.12656] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 01/30/2017] [Accepted: 01/31/2017] [Indexed: 12/28/2022]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral life cycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.
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Affiliation(s)
- Joseph T. Guidry
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| | - Christine E. Birdwell
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
| | - Rona S. Scott
- Department of Microbiology and Immunology, Center for Tumor and Molecular Virology, and Feist-Weiller Cancer Center. Louisiana State University Health Sciences Center-Shreveport. Shreveport, LA 71103
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49
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Wu CC, Fang CY, Huang SY, Chiu SH, Lee CH, Chen JY. Perspective: Contribution of Epstein-Barr virus (EBV) Reactivation to the Carcinogenicity of Nasopharyngeal Cancer Cells. Cancers (Basel) 2018; 10:cancers10040120. [PMID: 29673164 PMCID: PMC5923375 DOI: 10.3390/cancers10040120] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 04/02/2018] [Accepted: 04/12/2018] [Indexed: 12/30/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma derived from the epithelium of the post-nasal cavity, with a unique geographic and ethnic distribution. Epstein–Barr virus (EBV) is an etiological agent of NPC, but how it contributes to carcinogenesis is not completely clear. Although it is thought that EBV latency participates in the development of NPC, increasing evidence reveals that the lytic cycle also plays an important role in the carcinogenic process. In this review, we summarize our recent studies on how EBV reactivation causes genomic instability and accelerates tumorigenesis in epithelial cells. The roles of three lytic genes, namely, BRLF1, BGLF5 and BALF3, in this process are also introduced. Moreover, blocking EBV reactivation using natural compounds may help delay the progression of NPC tumorigenesis. These studies provide a new insight into NPC carcinogenesis and raise the possibility that inhibition of EBV reactivation may be a novel approach to prevent the relapse of NPC.
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Affiliation(s)
- Chung-Chun Wu
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan.
| | - Chih-Yeu Fang
- Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.
| | - Sheng-Yen Huang
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan.
| | - Shih-Hsin Chiu
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan.
| | - Chia-Huei Lee
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan.
| | - Jen-Yang Chen
- National Institute of Cancer Research, National Health Research Institutes, Zhunan 350, Taiwan.
- Department of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
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50
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Yang MJ, Guo J, Ye YF, Chen SH, Peng LX, Lin CY, Hu T, Xie SH, Xie CB, Huang QH, Lu YQ, Liu Q, Qian CN, Cao SM. Decreased macrophage inflammatory protein (MIP)-1α and MIP-1β increase the risk of developing nasopharyngeal carcinoma. Cancer Commun (Lond) 2018; 38:7. [PMID: 29764502 PMCID: PMC5993139 DOI: 10.1186/s40880-018-0279-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 09/28/2017] [Indexed: 12/15/2022] Open
Abstract
Background The association of circulating inflammation markers with nasopharyngeal carcinoma (NPC) is still largely unclear. This study aimed to comprehensively explore the relationship between circulating cytokine levels and the subsequent risk of NPC with a two-stage epidemiologic study in southern China. Methods The serum levels of 33 inflammatory cytokines were first measured in a hospital-based case–control study (150 NPC patients and 150 controls) using multiplex assay platforms. Marker levels were categorized into two or more groups based on the proportion of sample measurements that was above the lower limit of detection. Odds ratios (ORs) and 95% confidence intervals (CIs) relating the serum marker concentration to the risk of NPC were computed by multivariable logistic regression models. The associations were validated in 60 patients with NPC and 120 controls in a subsequent nested case–control study within a NPC screening trial. Potential interactions between serum cytokines and Epstein–Barr virus (EBV) relating to the risk of NPC were assessed using a likelihood ratio test. Results The levels of serum macrophage inflammatory protein (MIP)-1α and MIP-1β in the highest categories were associated with a decreased risk of NPC in both the case–control study (MIP-1α: OR = 0.49, 95% CI = 0.26–0.95; MIP-1β: OR = 0.47, 95% CI = 0.22–1.00) and the nested case–control study (MIP-1α: OR = 0.13, 95% CI = 0.03–0.62; MIP-1β: OR = 0.20, 95% CI = 0.04–0.94), compared with those in the lowest categories. Furthermore, individuals with lower levels of these two cytokine markers who were EBV seropositive presented with a largely higher risk of NPC compared with patients with higher levels who were EBV seronegative in both the case–control study (MIP-1α: OR = 16.28, 95% CI = 7.11–37.23; MIP-1β: OR = 12.86, 95% CI = 5.9–28.05) and the nested case–control study (MIP-1α: OR = 86.12, 95% CI = 10.58–701.03; MIP-1β: OR = 115.44, 95% CI = 13.92–957.73). Conclusions Decreased preclinical MIP-1α and MIP-1β levels might be associated with a subsequently increased risk of NPC. More mechanistic studies are required to fully understand this finding. Electronic supplementary material The online version of this article (10.1186/s40880-018-0279-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Meng-Jie Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Jie Guo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.,School of Public Health, Sun Yat-sen University, Guangzhou, 510060, Guangdong, P. R. China
| | - Yan-Fang Ye
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510060, Guangdong, P. R. China
| | - Sui-Hong Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Li-Xia Peng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Experimental Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Chu-Yang Lin
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Ting Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Shang-Hang Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Chuan-Bo Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Qi-Hong Huang
- Sihui Cancer Institute, Sihui, 526200, Guangdong, P. R. China
| | - Yu-Qiang Lu
- Sihui Cancer Institute, Sihui, 526200, Guangdong, P. R. China
| | - Qing Liu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China.,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Chao-Nan Qian
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. .,Department of Experimental Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.
| | - Su-Mei Cao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China. .,Department of Cancer Prevention Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.
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