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Zheng ZQ, Zhong CR, Wei CZ, Chen XJ, Chen GM, Nie RC, Chen ZW, Zhang FY, Li YF, Zhou ZW, Chen YM, Liang YL. Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants in EBV-Positive Gastric Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402284. [PMID: 38994917 PMCID: PMC11425274 DOI: 10.1002/advs.202402284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/26/2024] [Indexed: 07/13/2024]
Abstract
Although messenger RNA translation is tightly regulated to preserve protein synthesis and cellular homeostasis, chronic exposure to interferon-γ (IFN-γ) in several cancers can lead to tryptophan (Trp) shortage via the indoleamine-2,3-dioxygenase (IDO)- kynurenine pathway and therefore promotes the production of aberrant peptides by ribosomal frameshifting and tryptophan-to-phenylalanine (W>F) codon reassignment events (substitutants) specifically at Trp codons. However, the effect of Trp depletion on the generation of aberrant peptides by ribosomal mistranslation in gastric cancer (GC) is still obscure. Here, it is shows that the abundant infiltrating lymphocytes in EBV-positive GC continuously secreted IFN-γ, upregulated IDO1 expression, leading to Trp shortage and the induction of W>F substitutants. Intriguingly, the production of W>F substitutants in EBV-positive GC is linked to antigen presentation and the activation of the mTOR/eIF4E signaling pathway. Inhibiting either the mTOR/eIF4E pathway or EIF4E expression counteracted the production and antigen presentation of W>F substitutants. Thus, the mTOR/eIF4E pathway exposed the vulnerability of gastric cancer by accelerating the production of aberrant peptides and boosting immune activation through W>F substitutant events. This work proposes that EBV-positive GC patients with mTOR/eIF4E hyperactivation may benefit from anti-tumor immunotherapy.
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Affiliation(s)
- Zi-Qi Zheng
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Cheng-Rui Zhong
- Department of General Surgery, Hepatobiliary Pancreatic and Splenic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, P. R. China
| | - Cheng-Zhi Wei
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Xiao-Jiang Chen
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Guo-Ming Chen
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Run-Cong Nie
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Ze-Wei Chen
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Fei-Yang Zhang
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Yuan-Fang Li
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Yong-Ming Chen
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Ye-Lin Liang
- Department of Radiology Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
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Hirabayashi M, Georges D, Clifford GM, de Martel C. Estimating the Global Burden of Epstein-Barr Virus-Associated Gastric Cancer: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2023; 21:922-930.e21. [PMID: 35963539 DOI: 10.1016/j.cgh.2022.07.042] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Evidence suggests that a fraction of new gastric cancer cases may be etiologically associated with Epstein-Barr virus (EBV), a known carcinogenic agent. We aimed to systematically explore the proportion of EBV-positive gastric cancer. METHODS We did a systematic review (PROSPERO CRD42020164473) from January 1990 to August 2021. For each country and geographical region with available data, pooled prevalence and corresponding 95% confidence intervals (CIs) of EBV in gastric tumors were calculated for 3 subtypes of gastric adenocarcinoma (conventional adenocarcinoma, lymphoepithelioma-like gastric carcinoma, and remnant/stump carcinoma). For conventional adenocarcinoma, prevalence ratios (PRs) were presented for sex, Lauren's classification, gastric cancer stage, and anatomical location of the stomach. RESULTS In 220 eligible studies including over 68,000 cases of conventional gastric adenocarcinoma, EBV prevalence in tumor cells was 7.5% (95% CI, 6.9%-8.1%) and was higher in men compared with women (PR, 2.1; 95% CI, 1.9-2.4), in diffuse type compared with intestinal type (PR, 1.3; 95% CI, 1.1-1.5), and in the proximal region compared with the distal region (PR, 2.5; 95% CI, 2.0-3.1). There was no difference in EBV prevalence by gastric cancer stage. EBV prevalence was 75.9% (95% CI, 62.8%-85.5%) among lymphoepithelioma-like gastric carcinoma and 26.3% (95% CI, 22.2%-32.0%) among remnant or stump carcinoma. CONCLUSIONS Assuming a causal association between EBV and gastric cancer, our findings, when applied to the GLOBOCAN 2020 gastric cancer incidence, suggest that primary prevention such as the development of an effective EBV vaccine might prevent 81,000 EBV-associated gastric cancer cases worldwide annually.
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Affiliation(s)
- Mayo Hirabayashi
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Damien Georges
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Gary M Clifford
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Catherine de Martel
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France.
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de Souza CRT, Almeida MCA, Khayat AS, da Silva EL, Soares PC, Chaves LC, Burbano RMR. Association between Helicobacter pylori, Epstein-Barr virus, human papillomavirus and gastric adenocarcinomas. World J Gastroenterol 2018; 24:4928-4938. [PMID: 30487702 PMCID: PMC6250917 DOI: 10.3748/wjg.v24.i43.4928] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/11/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To correlate Helicobacter pylori (H. pylori), Epstein-Barr virus (EBV) and human papillomavirus (HPV) with gastric cancer (GC) cases in Pará State, Brazil.
METHODS Tissue samples were obtained from 302 gastric adenocarcinomas. A rapid urease test was used to detect the presence of H. pylori, and the presence of the cagA gene in the HP-positive samples was confirmed by PCR. An RNA in situ hybridization test designed to complement Eber1 RNA was used to detect the presence of EBV in the samples, and the L1 region of HPV was detected using nested PCR. Positive HPV samples were genotyped and analyzed for E6 and E7 viral gene expression. Infections were also correlated with the clinical and pathological characteristics of the patients.
RESULTS The majority of the 302 samples analyzed were obtained from men (65%) aged 55 years or older (67%) and were classified as the intestinal subtype (55%). All three pathogens were found in the samples analyzed in the present study (H. pylori: 87%, EBV: 20%, HPV: 3%). Overall, 78% of the H. pylori-positive (H. pylori+) samples were cagA+ (H. pylori-cagA+), and there was an association between the cytotoxic product of this gene and EBV. Coinfections of H. pylori-cagA+ and EBV were correlated with the most advanced tumor stages. Although only 20% of the tumors were positive for EBV, infection with this virus was associated with distant metastasis. Only the HPV 16 and 18 strains were found in the samples, although no expression of the E6 and E7 oncoproteins was detected. The fundus of the stomach was the region least affected by the pathogens.
CONCLUSION HPV was not involved in gastric tumorigenesis. Prophylactic and therapeutic measures against H. pylori and EBV may prevent the development of GC, especially the more aggressive forms.
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Affiliation(s)
| | - Marcelli Carolini Alves Almeida
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil
| | - André Salim Khayat
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil
- Oncology Research Center, Federal University of Pará, João de Barros Barreto University Hospital, Belém, Pará 66073-000, Brazil
| | - Emerson Lucena da Silva
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil
| | | | | | - Rommel Mario Rodríguez Burbano
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, Pará 66075-110, Brazil
- Oncology Research Center, Federal University of Pará, João de Barros Barreto University Hospital, Belém, Pará 66073-000, Brazil
- Ophir Loyola Hospital, Belém, Pará 66060-281, Brazil
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Geddert H, Zur Hausen A, Gabbert HE, Sarbia M. EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. Cell Oncol (Dordr) 2011; 34:209-14. [PMID: 20978327 DOI: 10.1007/s13402-011-0028-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2010] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric carcinomas (GC) constitute a distinct clinicopathological entity of gastric cancer. In order to determine underlying distinct aberrant promoter methylation we tested cardiac and non-cardiac GC with regard to the presence of EBV. METHODS One hundred GC were tested by RNA-in situ hybridization for the presence of EBV by EBV-encoded small RNA (EBER). Aberrant promoter methylation was investigated by methylation-specific real-time PCR for p16, p14, APC and hMLH1. P16 protein expression was assessed by immunohistochemistry. RESULTS In our selected study cohort, EBER-transcripts were detected in 19.6% (18/92) of GC. EBV-positive GC revealed significantly more often gene hypermethylation of p16, p14 and APC (p<0.0001, p<0.0001 and p=0.02, respectively) than EBV-negative GC. The majority of GC with p16 hypermethylation showed a p16 protein loss (22/28). In contrast, no correlation between the presence of EBV and hMLH1 hypermethylation was found (p=0.7). EBV-positive GC showed a trend towards non-cardiac location (p=0.06) and lower stages (I/II) according to the WHO (p=0.05). CONCLUSIONS Hypermethylation of tumor suppressor genes is significantly more frequent in EBV-associated GC compared to EBV-negative GC. Our data add new insights to the role of EBV in gastric carcinogenesis and underline that EBV-associated GC comprise a distinct molecular-pathologic as well as a distinct clinicopathological entity of GC.
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Affiliation(s)
- Helene Geddert
- Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany.
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Li S, Du H, Wang Z, Zhou L, Zhao X, Zeng Y. Meta-analysis of the relationship between Epstein-Barr virus infection and clinicopathological features of patients with gastric carcinoma. SCIENCE CHINA-LIFE SCIENCES 2010; 53:524-30. [PMID: 20596921 DOI: 10.1007/s11427-010-0082-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Accepted: 10/09/2009] [Indexed: 02/06/2023]
Abstract
Epstein-Barr virus (EBV) infection has been causally associated with occurrence of many malignant neoplasms. EBV-encoded small RNAs (EBERs) have been detected from about 10% of gastric carcinoma tissue cells, suggesting that EBV infection is associated with the development of gastric carcinoma. The present study pooled the data from the papers concerning EBV-related gastric cancers and performed a meta-analysis of 22 research papers. Among these papers, a total of 5475 cases with gastric cancer were enrolled, of whom 411 cases were found EBV-positive, with the EBV-positive rate being 7.5%. Among the EBV-positive gastric cancer cases, the detection rate was 11.1% in males and 3.0% in females. Compared with EBV-negative gastric cancer, EBV-positive gastric cancer had less lymph node metastasis. Based on the histological typing, of the EBV-positive gastric cancers, the diffuse type was 8.1%, and intestinal type was 8.0%. The examined specimen types included stored paraffin blocks and fresh surgically removed specimens, their EBV positive rates were 7.9% and 6.5% respectively. In terms of geographical distribution, the detection rate of EBV-positive gastric cancer was 9.4% in America, 6.1% in Asia and 9.1% in Europe. Meta-analysis showed that EBV infection occurred only in gastric cancer tissue cells and was significantly associated with the patients' gender, lymph node metastases, and the location where tumor tissue generated and geographical distribution (P<0.05), but was not significantly associated with the patients' histological types of tumor and the types of specimens (P>0.05). These results suggested that EBV-positive gastric cancer has distinct clinicopathological features.
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Affiliation(s)
- ShuYing Li
- College of Life Sciences, Hebei University, Baoding 071002, China
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Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 2009; 24:354-65. [PMID: 19335785 DOI: 10.1111/j.1440-1746.2009.05775.x] [Citation(s) in RCA: 189] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
There is conflicting data regarding the clinicopathological significance of the risk factors associated with Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC). To address this controversy, we performed a meta-analysis for the clinicopathological and molecular characteristics of EBVaGC. The relevant published studies were reviewed according to the defined selection criteria. The effect sizes of the outcome parameters were estimated by an odds ratio or a weighted mean difference. This meta-analysis included 48 studies that encompassed a total of 9738 patients. The frequency of EBVaGC was 8.8%, and EBVaGC was significantly associated with ethnicity. It was more predominant in men and in younger individuals. Interestingly, EBVaGC was more prevalent in Caucasian and Hispanic patients than in Asian ones. EBVaGC developed most often in the cardia and body, and it generally showed the diffuse histological type. EBV was highly prevalent in the patients with lymphoepithelial carcinoma. EBVaGC was closely associated with remnant cancer and a CpG island methylator-high status, but not with Helicobacter pylori infection, a TP53 expression, and p53 mutation. In addition, EBVaGC was not significantly associated with the depth of invasion, lymph node metastasis, or the clinical stage. The clinicopathological and molecular characteristics of EBVaGC are quite different from those of conventional gastric adenocarcinoma. However, further study is needed to determine the effect of EBV on the survival of EBVaGC patients.
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Affiliation(s)
- Ju-Han Lee
- Department of Pathology, Bioinformatics Interest Group, Korea University Ansan Hospital, Danwon-Gu, Ansan, Korea
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Uozaki H, Fukayama M. Epstein-Barr virus and gastric carcinoma--viral carcinogenesis through epigenetic mechanisms. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2008; 1:198-216. [PMID: 18784828 PMCID: PMC2480567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/13/2007] [Accepted: 09/20/2007] [Indexed: 05/26/2023]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) is the monoclonal growth of EBV-infected epithelial cells, and the entity was recognized only recently. EBV-associated GC is distributed worldwide and more than 90,000 patients are estimated to develop GC annually in association with EBV (10% of total GC). EBV-associated GC occurs in two forms in terms of the histological features, i.e., lymphoepithelioma-like GC and ordinary type of GC. Both share characteristic clinicopathological features, such as the preferential occurrence as multiple cancer and remnant stomach cancer. While the expression of EBV-latent genes is restricted to several in the infected cells (Latency I), EBV-associated GC shows gastric cell phenotype, resistance to apoptosis, and the production of immunomodulator molecules. Recently, global and non-random CpG island methylation of the promoter region of many cancer-related genes has been demonstrated with their decreased expression, such as p16 INK4A, p73 and E-cadherin. This abnormality is accompanied by methylation of the EBV genome itself, suggesting a process of virus-driven hypermethylation in the development of neoplastic cells. Further studies are necessary to determine the precise sequence of EBV infection, methylation, transformation and selection of the predominant clone within the stomach mucosa. Future studies are also desirable for the target and strategy of therapy, such as initiating viral replication or reversing the DNA methylation of cellular genes.
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Affiliation(s)
- Hiroshi Uozaki
- Department of Pathology, Graduate School of Medicine, The University of Tokyo Bunkyo-ku, Tokyo, Japan
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Gao Y, Ji J, Zhu W, Wang Y, Luo B. Influence of Epstein-Barr virus latent membrane protein 2A on the proliferation of human gastric cancer cells. Shijie Huaren Xiaohua Zazhi 2007; 15:108-113. [DOI: 10.11569/wcjd.v15.i2.108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To construct recombinant adenovirus expression vector containing Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) and investigate the effects of LMP2A on the proliferation of human gastric cancer cell line.
METHODS: The target gene LMP2A was amplified by reverse transcription-polymerase chain reaction (RT-PCR), and the recombinant adenovirus vector carrying LMP2A gene was constructed with AdEasy system. The recombinant adenovirus vector pAd-2A was transfected into HEK293 cells with lipofectamine 2000 to package recombinant adenovirus, and then gastric cancer cells SGC with negative EBV were infected by recombinant adenovirus. The expression of LMP2A and its effect on the proliferation of SGC cells were analyzed by PT-PCR, MTT assay, fluorescence activated cell sorting (FACS) and confocal microscopy.
RESULTS: The recombinant adenovirus vector pAd-2A was successfully constructed and identified by PCR, restrictive enzyme analysis, and DNA sequencing. The recombinant adenovirus vAd-2A packaged by HEK293 cells had stable infectivity. The virus titer was 3.16×1012 pfu/L. MTT assay, FACS and confocal microscopy showed that vAd-2A transfection significantly increased the proliferation of SGC cells (P < 0.01). The ratio of S-phase cells was markedly elevated after vAd-2A transfection in comparison with that after vAd transfection and non-transfection (24 h: 35.2% ± 5.1% vs 14.0% ± 3.4%, 13.2% ± 4.6%, P < 0.01; 48 h: 25.6% ± 4.1% vs 12.9% ± 2.6%, 12.5% ± 3.2%, P < 0.01). The expression of Cyclin E protein was also induced by LMP2A.
CONCLUSION: The recombinant adenovirus vector carrying EBV LMP2A gene is constructed successfully. Meanwhile, it is confirmed that LMP2A may promote the proliferation of SGC cells by induction of Cyclin E expression.
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