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Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.
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Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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Qin S, Chen H, Tian C, Chen Z, Zuo L, Zhang X, Hao H, Huang F, Liu H, Sun X, Guan W. NS1-mediated DNMT1 degradation regulates human bocavirus 1 replication and RNA processing. PLoS Pathog 2024; 20:e1012682. [PMID: 39541416 PMCID: PMC11594422 DOI: 10.1371/journal.ppat.1012682] [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: 09/16/2024] [Revised: 11/26/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
Methylation of the DNA genome plays an important role in viral gene inactivation. However, the role of DNA methylation in human bocavirus (HBoV) remains unclear. In this study, the HBoV1 genomic DNA was found extensively methylated at the CHG and CHH sites. Inhibiting DNA methylation with 5-aza-2'-deoxycytidine (DAC) altered the methylation status and reduced viral DNA production, while enhanced the RNA splicing at D1 and D3 sites and the polyadenylation at the proximal polyadenylation site, (pA)p. Knockdown of DNA methyltransferase 1 (DNMT1) had the same effect on viral DNA synthesis and RNA processing as the DAC treatment, indicating that DNMT1 is the major host methyltransferase involved in viral DNA methylation. In addition, the nonstructural protein NS1 promoted DNMT1 degradation through the ubiquitin-proteasome pathway to regulate viral replication and RNA processing. Collectively, the results suggest that DNA methylation and DNMT1 facilitate HBoV replication and are essential for appropriate NS1 localization in the nucleus. DNMT1 degradation through NS1 promotes the virus RNA processing, leading to viral protein expression.
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Affiliation(s)
- Shuangkang Qin
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Honghe Chen
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Chuchu Tian
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Zhen Chen
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Li Zuo
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xueyan Zhang
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Haojie Hao
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Hubei JiangXia Laboratory, Wuhan, Hubei, China
| | - Fang Huang
- Hubei JiangXia Laboratory, Wuhan, Hubei, China
| | - Haibin Liu
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Hubei JiangXia Laboratory, Wuhan, Hubei, China
| | - Xiulian Sun
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Wuxiang Guan
- Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Hubei JiangXia Laboratory, Wuhan, Hubei, China
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3
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Dong W, Wang H, Li M, Li P, Ji S. Virus-induced host genomic remodeling dysregulates gene expression, triggering tumorigenesis. Front Cell Infect Microbiol 2024; 14:1359766. [PMID: 38572321 PMCID: PMC10987825 DOI: 10.3389/fcimb.2024.1359766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/01/2024] [Indexed: 04/05/2024] Open
Abstract
Virus-induced genomic remodeling and altered gene expression contribute significantly to cancer development. Some oncogenic viruses such as Human papillomavirus (HPV) specifically trigger certain cancers by integrating into the host's DNA, disrupting gene regulation linked to cell growth and migration. The effect can be through direct integration of viral genomes into the host genome or through indirect modulation of host cell pathways/proteins by viral proteins. Viral proteins also disrupt key cellular processes like apoptosis and DNA repair by interacting with host molecules, affecting signaling pathways. These disruptions lead to mutation accumulation and tumorigenesis. This review focuses on recent studies exploring virus-mediated genomic structure, altered gene expression, and epigenetic modifications in tumorigenesis.
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Affiliation(s)
- Weixia Dong
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Huiqin Wang
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Menghui Li
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Ping Li
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
| | - Shaoping Ji
- Department of Basic Medicine, Zhengzhou Shuqing Medical College, Zhengzhou, Henan, China
- Department of Biochemistry and Molecular Biology, Medical School, Henan University, Kaifeng, Henan, China
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4
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Torne AS, Robertson ES. Epigenetic Mechanisms in Latent Epstein-Barr Virus Infection and Associated Cancers. Cancers (Basel) 2024; 16:991. [PMID: 38473352 PMCID: PMC10931536 DOI: 10.3390/cancers16050991] [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: 01/31/2024] [Revised: 02/25/2024] [Accepted: 02/25/2024] [Indexed: 03/14/2024] Open
Abstract
The Epstein-Barr Virus (EBV) is a double-stranded DNA-based human tumor virus that was first isolated in 1964 from lymphoma biopsies. Since its initial discovery, EBV has been identified as a major contributor to numerous cancers and chronic autoimmune disorders. The virus is particularly efficient at infecting B-cells but can also infect epithelial cells, utilizing an array of epigenetic strategies to establish long-term latent infection. The association with histone modifications, alteration of DNA methylation patterns in host and viral genomes, and microRNA targeting of host cell factors are core epigenetic strategies that drive interactions between host and virus, which are necessary for viral persistence and progression of EBV-associated diseases. Therefore, understanding epigenetic regulation and its role in post-entry viral dynamics is an elusive area of EBV research. Here, we present current outlooks of EBV epigenetic regulation as it pertains to viral interactions with its host during latent infection and its propensity to induce tumorigenesis. We review the important epigenetic regulators of EBV latency and explore how the strategies involved during latent infection drive differential epigenetic profiles and host-virus interactions in EBV-associated cancers.
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Affiliation(s)
| | - Erle S. Robertson
- Tumor Virology Program, Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
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Mostaghimi T, Bahadoran E, Bakht M, Taheri S, Sadeghi H, Babaei A. Role of lncRNAs in Helicobacter pylori and Epstein-Barr virus associated gastric cancers. Life Sci 2024; 336:122316. [PMID: 38035995 DOI: 10.1016/j.lfs.2023.122316] [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: 09/30/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
Helicobacter pylori infection is a risk factor for the development of gastric cancer (GC), and the role of co-infection with viruses, such as Epstein-Barr virus, in carcinogenesis cannot be ignored. Furthermore, it is now known that genetic factors such as long non-coding RNAs (lncRNAs) are involved in many diseases, including GC. On the other side, they can also be used as therapeutic goals. Modified lncRNAs can cause aberrant expression of genes encoding proximal proteins, which are essential for the development of carcinoma. In this review, we present the most recent studies on lncRNAs in GC, concentrating on their roles in H. pylori and EBV infections, and discuss some of the molecular mechanisms of these GC-related pathogens. There was also a discussion of the research gaps and future perspectives.
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Affiliation(s)
- Talieh Mostaghimi
- Department of Medical Microbiology and Biotechnology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Ensiyeh Bahadoran
- School of Medicine, Qazvin University of Medical Science, Qazvin, Iran
| | - Mehdi Bakht
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Shiva Taheri
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Hamid Sadeghi
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran
| | - Abouzar Babaei
- Medical Microbiology Research Center, Qazvin University of Medical Science, Qazvin, Iran.
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Huang X, Zhang M, Zhang Z. The Role of LMP1 in Epstein-Barr Virus-associated Gastric Cancer. Curr Cancer Drug Targets 2024; 24:127-141. [PMID: 37183458 DOI: 10.2174/1568009623666230512153741] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 05/16/2023]
Abstract
EBV promotes many cancers such as lymphoma, nasopharyngeal carcinoma, and gastric; Latent Membrane Protein 1 (LMP1) is considered to be a major oncogenic protein encoded by Epstein- Barr virus (EBV). LMP1 functions as a carcinogen in lymphoma and nasopharyngeal carcinoma, and LMP1 may also promote gastric cancer. The expression level of LMP1 in host cells is a key determinant in tumorigenesis and maintenance of virus specificity. By promoting cell immortalization and cell transformation, promoting cell proliferation, affecting immunity, and regulating cell apoptosis, LMP1 plays a crucial tumorigenic role in epithelial cancers. However, very little is currently known about LMP1 in Epstein-Barr virus-associated gastric cancer (EBVaGC); the main reason is that the expression level of LMP1 in EBVaGC is comparatively lower than other EBV-encoded proteins, such as The Latent Membrane Protein 2A (LMP2A), Epstein-Barr nuclear antigen 1 (EBNA1) and BamHI-A rightward frame 1 (BARF1), to date, there are few studies related to LMP1 in EBVaGC. Recent studies have demonstrated that LMP1 promotes EBVaGC by affecting The phosphatidylinositol 3-kinase- Akt (PI3K-Akt), Nuclear factor-kappa B (NF-κB), and other signaling pathways to regulate many downstream targets such as Forkhead box class O (FOXO), C-X-C-motif chemokine receptor (CXCR), COX-2 (Cyclooxygenase-2); moreover, the gene methylation induced by LMP1 in EBVaGC has become one of the characteristics that distinguish this gastric cancer (GC) from other types of gastric cancer and LMP1 also promotes the formation of the tumor microenvironment (TME) of EBVaGC in several ways. This review synthesizes previous relevant literature, aiming to highlight the latest findings on the mechanism of action of LMP1 in EBVaGC, summarize the function of LMP1 in EBVaGC, lay the theoretical foundation for subsequent new research on LMP1 in EBVaGC, and contribute to the development of novel LMP1-targeted drugs.
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Affiliation(s)
- Xinqi Huang
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Meilan Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiwei Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
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7
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Shareena G, Kumar D. Epigenetics of Epstein Barr virus - A review. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166838. [PMID: 37544529 DOI: 10.1016/j.bbadis.2023.166838] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 07/14/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023]
Abstract
Epstein Barr is the first-in-human oncogenic virus, closely related to numerous lymphoproliferative and malignant diseases, including HL, BL, NPC, and GC. EBV establishes life-long persistence infection portraying a biphasic viral life cycle: latent period and lytic replication. B-cells serve as critical regions for EBV latent genes, wherein viral gene expression is suppressed, promoting viral genome maintenance and immune recognition evasion. Upon its lytic reactivation, viral gene expression induces its replication, progeny production, and transmission. Dysregulations of epigenetic regulation in expressions of TSGs lead to carcinogenesis. Several studies reveal that EBV is associated with aberrant viral DNA and host genome methylation patterns, promoting immune monitoring, recognition evasiveness and host cell persistence. Among other epigenetic modifications, DNA methylation suppresses the majority of viral latent gene promoters, sparing a few, and acts as a prerequisite for activating EBV's lytic cycle, giving rise to viral progeny. It affects the host's epigenome via reprogramming cells to oncogenic, long-lasting phenotypes, as evident in several malignancies. At each phase of its life cycle, EBV exploits cellular mechanisms of epigenetic regulation, implying its unique host-pathogen relationship. This review summarized the DNA methylation's regulatory roles on several EBV-related promoter regions, along with the host genome in pathological conditions, highlights viral genes involved in a latent, lytic and latent-lytic phase of EBV infection. Moreover, it provides diagrammatic insights into methylation-based pathways in EBV.
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Affiliation(s)
- Gadde Shareena
- Poona College of Pharmacy, Department of Pharmaceutical Chemistry, Bharati Vidyapeeth (Deemed to be University), Erandwane, Pune 411038, Maharashtra, India
| | - Dileep Kumar
- Poona College of Pharmacy, Department of Pharmaceutical Chemistry, Bharati Vidyapeeth (Deemed to be University), Erandwane, Pune 411038, Maharashtra, India; UC Davis Comprehensive Cancer Center, Department of Entomology and Nematology, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
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8
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Liu T, Zhou X, Zhang Z, Qin Y, Wang R, Qin Y, Huang Y, Mo Y, Huang T. The role of EBV-encoded miRNA in EBV-associated gastric cancer. Front Oncol 2023; 13:1204030. [PMID: 37388232 PMCID: PMC10301731 DOI: 10.3389/fonc.2023.1204030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 05/31/2023] [Indexed: 07/01/2023] Open
Abstract
Epstein-Barr virus (human herpesvirus 4, EBV) is a linear double-stranded DNA virus that infects over 90% of the population worldwide. However, our understanding of EBV's contribution to tumorigenesis of EBV-associated GC (EBVaGC) remains incomplete. Recent advancements in EBVaGC research have highlighted that EBV-encoded microRNAs (miRNAs) play prominent roles in critical cellular processes such as migration, cell cycle, apoptosis, cell proliferation, immune response, and autophagy. Notably, the largest group of EBV-encoded miRNAs, known as BamHI-A rightward transcripts (BARTs), exhibit bidirectional effects in EBVaGC. For instance, they present both anti-apoptotic and pro-apoptotic functions and enhance chemosensitivity while also conferring resistance to 5-fluorouracil. Despite these findings, the comprehensive mechanisms through which miRNAs contribute to EBVaGC are yet to be fully elucidated. In this work, we summarize the current evidence of the roles of miRNA in EBVaGC, particularly with the application of multi-omic techniques. Additionally, we discuss the application of miRNA in EBVaGC in retrospective analyses and provide novel perspectives on the use of miRNA in EBVaGC in translational medicine.
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Affiliation(s)
- Ting Liu
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaoying Zhou
- Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
| | - Zhe Zhang
- Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
- Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yutao Qin
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Rensheng Wang
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
| | - Yanning Qin
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Yuqi Huang
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Yingxi Mo
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tingting Huang
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Guangxi Medical University, Nanning, China
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9
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Wah NW, Mok Y, Omar N, Chang KTE, Tay TKY, Hue SSS, Lee VKM. Clinicopathologic and Molecular Characteristics of Epstein-Barr Virus-Associated Smooth Muscle Tumor Compared With Those of Leiomyoma and Leiomyosarcoma. Mod Pathol 2023; 36:100127. [PMID: 36965331 DOI: 10.1016/j.modpat.2023.100127] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/28/2022] [Accepted: 01/31/2023] [Indexed: 02/11/2023]
Abstract
Epstein-Barr virus (EBV)-associated smooth muscle tumors (EBV-SMTs) are rare smooth muscle neoplasms exclusively associated with immunosuppression, such as in patients with HIV/AIDS, posttransplant, and congenital immunodeficiency. However, the genomic landscape of EBV-SMTs is poorly understood. Leiomyosarcomas harbor genomic instability and multiple recurrent DNA copy number alterations, whereas leiomyomas lack such changes. Thus, this study aimed to fill this knowledge gap by characterizing copy number alterations in EBV-SMTs and correlating this information with clinicopathologic characteristics. Our study investigated and compared the pathologic characteristics and copy number profiles of 9 EBV-SMTs (from 7 post-transplant and AIDS patients), 6 leiomyomas, and 7 leiomyosarcomas, using chromosomal microarray platforms. Our results showed a lower copy number alteration burden in EBV-SMTs and leiomyoma than in leiomyosarcoma. This contrast in the molecular profile between EBV-SMTs and leiomyosarcoma is concordant with the different clinical behaviors and pathologic characteristics exhibited by these tumors. Despite having an overall copy number alteration profile closer to leiomyoma, recurrent copy number gain of oncogenes, such as RUNX1, CCND2, and ETS2, was found in EBV-SMTs. Epigenetic alterations may play an important role in tumorigenesis as recurrent copy number gains were found in histone deacetylases. A gene enrichment analysis also demonstrated enrichment of genes involved in the host response to viral infection, suggesting that the tumor immune microenvironment may play an important role in EBV-SMT tumorigenesis.
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Affiliation(s)
- Naw Wah Wah
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Yingting Mok
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pathology, National University Hospital, National University Health System, Singapore; Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore
| | | | - Kenneth Tou En Chang
- Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore
| | | | - Susan Swee-Shan Hue
- Department of Pathology, National University Hospital, National University Health System, Singapore
| | - Victor Kwan Min Lee
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Salnikov MY, Wang E, Christensen E, Prusinkiewicz MA, Shooshtari P, Mymryk JS. The EBV Gastric Cancer Resource (EBV-GCR): A Suite of Tools for Investigating EBV-Associated Human Gastric Carcinogenesis. Viruses 2023; 15:v15040853. [PMID: 37112833 PMCID: PMC10145221 DOI: 10.3390/v15040853] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Epstein-Barr virus (EBV) causes lifelong infection in over 90% of the world’s population. EBV infection leads to several types of B cell and epithelial cancers due to the viral reprogramming of host-cell growth and gene expression. EBV is associated with 10% of stomach/gastric adenocarcinomas (EBVaGCs), which have distinct molecular, pathological, and immunological characteristics compared to EBV-negative gastric adenocarcinomas (EBVnGCs). Publicly available datasets, such as The Cancer Genome Atlas (TCGA), contain comprehensive transcriptomic, genomic, and epigenomic data for thousands of primary human cancer samples, including EBVaGCs. Additionally, single-cell RNA-sequencing data are becoming available for EBVaGCs. These resources provide a unique opportunity to explore the role of EBV in human carcinogenesis, as well as differences between EBVaGCs and their EBVnGC counterparts. We have constructed a suite of web-based tools called the EBV Gastric Cancer Resource (EBV-GCR), which utilizes TCGA and single-cell RNA-seq data and can be used for research related to EBVaGCs. These web-based tools allow investigators to gain in-depth biological and clinical insights by exploring the effects of EBV on cellular gene expression, associations with patient outcomes, immune landscape features, and differential gene methylation, featuring both whole-tissue and single-cell analyses.
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Affiliation(s)
- Mikhail Y. Salnikov
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
| | - Eric Wang
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
| | - Erik Christensen
- Department of Computer Science, Western University, London, ON N6A 5B7, Canada
- Children’s Health Research Institute, Lawson Health Research Institute, London, ON N6A 5W9, Canada
| | | | - Parisa Shooshtari
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- Department of Computer Science, Western University, London, ON N6A 5B7, Canada
- Children’s Health Research Institute, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- The Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
| | - Joe S. Mymryk
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Otolaryngology, Western University, London, ON N6A 5W9, Canada
- Correspondence:
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11
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Abe K, Kitago M, Matsuda S, Shinoda M, Yagi H, Abe Y, Oshima G, Hori S, Endo Y, Yokose T, Miura E, Kubota N, Ueno A, Masugi Y, Ojima H, Sakamoto M, Kitagawa Y. Epstein-Barr virus-associated inflammatory pseudotumor variant of follicular dendritic cell sarcoma of the liver: a case report and review of the literature. Surg Case Rep 2022; 8:220. [PMID: 36484868 PMCID: PMC9733763 DOI: 10.1186/s40792-022-01572-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 11/22/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Follicular dendritic cell sarcoma is a rare stromal tumor with no standard treatment. However, some reports have revealed that follicular dendritic cell sarcoma has an inflammatory pseudotumor variant associated with Epstein-Barr virus infection that has a relatively good prognosis. In this report, we present a case of a resected inflammatory pseudotumor variant of follicular dendritic cell sarcoma of the liver, and have reviewed the literature on the clinicopathological, molecular, and genomic features of this tumor. CASE PRESENTATION The inflammatory pseudotumor variant of follicular dendritic cell sarcoma originates only in the liver or spleen, causes no symptoms, and is more common in middle-aged Asian women. It has no characteristic imaging features, which partially explains why the inflammatory pseudotumor variant of follicular dendritic cell sarcoma is difficult to diagnose. Pathologically, the inflammatory pseudotumor variant of follicular dendritic cell sarcoma has spindle cells mixed with inflammatory cells and is variably positive for follicular dendritic cell markers (CD21, CD23, and CD35) and Epstein-Barr virus-encoded RNA. On genetic analysis, patients with this tumor high levels of latent membrane protein 1 gene expression and extremely low levels of host C-X-C Chemokine Receptor type 7 gene expression, indicating that the inflammatory pseudotumor variant of follicular dendritic cell sarcoma has a latent Epstein-Barr virus type 2 infection. CONCLUSIONS The inflammatory pseudotumor variant of follicular dendritic cell sarcoma is an Epstein-Barr virus-associated tumor and a favorable prognosis by surgical resection, similar to Epstein-Barr virus-associated gastric cancer.
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Affiliation(s)
- K. Abe
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - M. Kitago
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - S. Matsuda
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - M. Shinoda
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - H. Yagi
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - Y. Abe
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - G. Oshima
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - S. Hori
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - Y. Endo
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - T. Yokose
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
| | - E. Miura
- grid.26091.3c0000 0004 1936 9959Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - N. Kubota
- grid.26091.3c0000 0004 1936 9959Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - A. Ueno
- grid.26091.3c0000 0004 1936 9959Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Y. Masugi
- grid.26091.3c0000 0004 1936 9959Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - H. Ojima
- grid.26091.3c0000 0004 1936 9959Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - M. Sakamoto
- grid.26091.3c0000 0004 1936 9959Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Y. Kitagawa
- grid.26091.3c0000 0004 1936 9959Department of Surgery, Keio University School of Medicine, Shinanomachi 35, Shinjuku-Ku, Tokyo, 160-8582 Japan
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12
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MC180295 Inhibited Epstein–Barr Virus-Associated Gastric Carcinoma Cell Growth by Suppressing DNA Repair and the Cell Cycle. Int J Mol Sci 2022; 23:ijms231810597. [PMID: 36142506 PMCID: PMC9500863 DOI: 10.3390/ijms231810597] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/29/2022] [Accepted: 09/08/2022] [Indexed: 11/16/2022] Open
Abstract
DNA methylation of both viral and host DNA is one of the major mechanisms involved in the development of Epstein–Barr virus-associated gastric carcinoma (EBVaGC); thus, epigenetic treatment using demethylating agents would seem to be promising. We have verified the effect of MC180295, which was discovered by screening for demethylating agents. MC180295 inhibited cell growth of the EBVaGC cell lines YCCEL1 and SNU719 in a dose-dependent manner. In a cell cycle analysis, growth arrest and apoptosis were observed in both YCCEL1 and SNU719 cells treated with MC180295. MKN28 cells infected with EBV were sensitive to MC180295 and showed more significant inhibition of cell growth compared to controls without EBV infection. Serial analysis of gene expression analysis showed the expression of genes belonging to the role of BRCA1 in DNA damage response and cell cycle control chromosomal replication to be significantly reduced after MC180295 treatment. We confirmed with quantitative PCR that the expression levels of BRCA2, FANCM, RAD51, TOP2A, and CDC45 were significantly decreased by MC180295. LMP1 and BZLF1 are EBV genes with expression that is epigenetically regulated, and MC180295 could up-regulate their expression. In conclusion, MC180295 inhibited the growth of EBVaGC cells by suppressing DNA repair and the cell cycle.
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13
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CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases. Pathogens 2022; 11:pathogens11080831. [PMID: 35894054 PMCID: PMC9330826 DOI: 10.3390/pathogens11080831] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 11/17/2022] Open
Abstract
Activated cytotoxic CD4 T cells (HLA-DR+) play an important role in the control of EBV infection, especially in cells with latency I (EBNA-1). One of the evasion mechanisms of these latency cells is generated by gp42, which, via peripherally binding to the β1 domain of the β chain of MHC class II (HLA-DQ, -DR, and -DP) of the infected B lymphocyte, can block/alter the HLA class II/T-cell receptor (TCR) interaction, and confer an increased level of susceptibility towards the development of EBV-associated autoimmune diseases or cancer in genetically predisposed individuals (HLA-DRB1* and DQB1* alleles). The main developments predisposing the factors of these diseases are: EBV infection; HLA class II risk alleles; sex; and tissue that is infiltrated with EBV-latent cells, forming ectopic lymphoid structures. Therefore, there is a need to identify treatments for eliminating cells with EBV latency, because the current treatments (e.g., antivirals and rituximab) are ineffective.
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14
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Fierti AO, Yakass MB, Okertchiri EA, Adadey SM, Quaye O. The Role of Epstein-Barr Virus in Modulating Key Tumor Suppressor Genes in Associated Malignancies: Epigenetics, Transcriptional, and Post-Translational Modifications. Biomolecules 2022; 12:biom12010127. [PMID: 35053275 PMCID: PMC8773690 DOI: 10.3390/biom12010127] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/27/2021] [Accepted: 01/05/2022] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus (EBV) is ubiquitous and carried by approximately 90% of the world’s adult population. Several mechanisms and pathways have been proposed as to how EBV facilitates the pathogenesis and progression of malignancies, such as Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric cancers, the majority of which have been linked to viral proteins that are expressed upon infection including latent membrane proteins (LMPs) and Epstein-Barr virus nuclear antigens (EBNAs). EBV expresses microRNAs that facilitate the progression of some cancers. Mostly, EBV induces epigenetic silencing of tumor suppressor genes, degradation of tumor suppressor mRNA transcripts, post-translational modification, and inactivation of tumor suppressor proteins. This review summarizes the mechanisms by which EBV modulates different tumor suppressors at the molecular and cellular levels in associated cancers. Briefly, EBV gene products upregulate DNA methylases to induce epigenetic silencing of tumor suppressor genes via hypermethylation. MicroRNAs expressed by EBV are also involved in the direct targeting of tumor suppressor genes for degradation, and other EBV gene products directly bind to tumor suppressor proteins to inactivate them. All these processes result in downregulation and impaired function of tumor suppressors, ultimately promoting malignances.
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15
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Molecular Basis of Epstein-Barr Virus Latency Establishment and Lytic Reactivation. Viruses 2021; 13:v13122344. [PMID: 34960613 PMCID: PMC8706188 DOI: 10.3390/v13122344] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/27/2022] Open
Abstract
Epstein–Barr virus (EBV) is a causative agent of infectious mononucleosis and several types of cancer. Like other herpesviruses, it establishes an asymptomatic, life-long latent infection, with occasional reactivation and shedding of progeny viruses. During latency, EBV expresses a small number of viral genes, and exists as an episome in the host–cell nucleus. Expression patterns of latency genes are dependent on the cell type, time after infection, and milieu of the cell (e.g., germinal center or peripheral blood). Upon lytic induction, expression of the viral immediate-early genes, BZLF1 and BRLF1, are induced, followed by early gene expression, viral DNA replication, late gene expression, and maturation and egress of progeny virions. Furthermore, EBV reactivation involves more than just progeny production. The EBV life cycle is regulated by signal transduction, transcription factors, promoter sequences, epigenetics, and the 3D structure of the genome. In this article, the molecular basis of EBV latency establishment and reactivation is summarized.
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16
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Ruiz-Pablos M, Paiva B, Montero-Mateo R, Garcia N, Zabaleta A. Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol 2021; 12:656797. [PMID: 34867935 PMCID: PMC8634673 DOI: 10.3389/fimmu.2021.656797] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 10/19/2021] [Indexed: 01/04/2023] Open
Abstract
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approximately 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. This is probably related to the limited knowledge about its origin. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiology of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-associated autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiology generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.
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Affiliation(s)
| | - Bruno Paiva
- Clinica Universidad de Navarra, Centro de Investigación Medica Aplicada (CIMA), IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | | | - Nicolas Garcia
- Clinica Universidad de Navarra, Centro de Investigación Medica Aplicada (CIMA), IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
| | - Aintzane Zabaleta
- Clinica Universidad de Navarra, Centro de Investigación Medica Aplicada (CIMA), IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
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17
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He M, Yue L, Wang H, Yu F, Yu M, Ni P, Zhang K, Chen S, Duan G, Zhang R. Evaluation of the prognostic value of CBXs in gastric cancer patients. Sci Rep 2021; 11:12375. [PMID: 34117289 PMCID: PMC8196000 DOI: 10.1038/s41598-021-91649-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Accepted: 04/26/2021] [Indexed: 12/23/2022] Open
Abstract
Chromobox (CBX) proteins were suggested to exert epigenetic regulatory and transcriptionally repressing effects on target genes and might play key roles in the carcinogenesis of a variety of carcinomas. Nevertheless, the functions and prognostic significance of CBXs in gastric cancer (GC) remain unclear. The current study investigated the roles of CBXs in the prognosis of GC using the Oncomine, The Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, The Cancer Genome Atlas (TCGA), and cBioPortal databases. CBX1/2/3/4/5 were significantly upregulated in GC tissues compared with normal tissues, and CBX7 was downregulated. Multivariate analysis showed that high mRNA expression levels of CBX3/8 were independent prognostic factors for prolonged OS in GC patients. In addition, the genetic mutation rate of CBXs was 37% in GC patients, and genetic alterations in CBXs showed no association with OS or disease-free survival (DFS) in GC patients. These results indicated that CBX3/8 can be prognostic biomarkers for the survival of GC patients.
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Affiliation(s)
- Mengya He
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Limin Yue
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China.
| | - Haiyan Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Feiyan Yu
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Mingyang Yu
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Peng Ni
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Ke Zhang
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Shuaiyin Chen
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China
| | - Guangcai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China.
| | - Rongguang Zhang
- Department of Epidemiology, College of Public Health, Hainan Medical University, Longhua District, No.3 Xueyuan Road, Haikou, 570216, China.
- Department of Experimentation Center, College of Public Health, Zhengzhou University, No.100 Kexue Avenue, Zhengzhou, 450001, China.
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18
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Expression of MAP9 in Epstein-Barr virus-associated gastric carcinoma. Virus Res 2020; 293:198253. [PMID: 33309912 DOI: 10.1016/j.virusres.2020.198253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/24/2020] [Accepted: 11/25/2020] [Indexed: 12/27/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) comprises approximately 9% of all cases of GC. EBV-associated GC (EBVaGC) has characteristic clinicopathological features for a favorable prognosis. Microtubule-associated protein 9 (MAP9) is a cell cycle-associated gene required for bipolar spindle assembly, mitosis progression, and cytokinesis. Nevertheless, to date, there have been no reports on MAP9 function in EBVaGC. In this study, we demonstrated that the mRNA and protein levels of MAP9 were up-regulated in EBV-positive gastric carcinoma cell lines. The positive rate of MAP9 expression in EBVaGC tissues was shown to be significantly higher than that in EBV-negative gastric carcinoma (EBVnGC) tissues. Additionally, the expression of MAP9 was partly increased in EBVnGC cell lines by interfering with DNA methyltransferase 1 (DNMT1) or treated with 5-aza-2'-deoxycytidine. Thus, EBV may regulate MAP9 expression by modifying the methylation of MAP9 CpG islands through DNMT1. By inhibiting the expression of MAP9 with small interfere sequence in the EBV-positive GC cell line GT38 and overexpressing MAP9 in the EBV-negative GC cell line AGS, we demonstrated that MAP9 inhibited the growth and induced apoptosis of EBVaGC cells significantly. In conclusion, our study demonstrated that EBV can up-regulate the expression of MAP9 in EBVaGC, and the methylation of MAP9 CpG islands influences this regulation. And MAP9 acts as a tumor suppressor in the development of EBVaGC.
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19
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Armenta-Quiroga AS, Khalid R, Dhalla PS, Garcia J, Bapatla A, Kaul A, Khan S. Essential Genes to Consider in Epstein-Barr Virus-Associated Gastric Cancer: A Systematic Review. Cureus 2020; 12:e11610. [PMID: 33364127 PMCID: PMC7752788 DOI: 10.7759/cureus.11610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Gastric cancer (GC) is a prevalent malignancy worldwide; the Epstein-Barr Virus (EBV) also affects many people worldwide. An important association has been seen in these two diseases that could explain causality and a possible viral etiology of GC as has been seen with Helicobacter pylori. This study aims to identify genes expressed in malignant cells that are infected with EBV and see if one could be more oncogenic than the other. We conducted a systematic review based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. We had 29 observational studies after inclusion/exclusion criteria and quality assessment for every single study. A total of 1022 patients were evaluated for different types of genes in 29 papers. It was demonstrated that the most expressed genes or the gene most involved were genes that are seen in Epstein-Barr virus-associated gastric cancer (EBVaGC) as latent genes of the EBV-infected cells, which are found in tumor cells. The genes that were mostly involved were LMP2, BNLF2a, and the absence of LMP1 that lead to the expression of BARF1, among other genes. These studies were made on mostly Asian populations, so it is still unknown if these genes involved have a geographical association more than an EBV and GC association.
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Affiliation(s)
- Ana S Armenta-Quiroga
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Raheela Khalid
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Jian Garcia
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Anusha Bapatla
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Arunima Kaul
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Safeera Khan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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20
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Kiso M, Urabe Y, Ito M, Masuda K, Boda T, Kotachi T, Hata K, Yorita N, Nagasaki N, Abduwali M, Hiyama Y, Oka S, Tanaka S, Chayama K. Clinical and genomic characteristics of mucosal signet-ring cell carcinoma in Helicobacter pylori-uninfected stomach. BMC Gastroenterol 2020; 20:243. [PMID: 32727394 PMCID: PMC7391816 DOI: 10.1186/s12876-020-01387-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 07/16/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Gastric cancer develops even in Helicobacter pylori(H. pylori)-uninfected patients and its typical histological feature is signet ring cell carcinoma (SRCC) within the mucosal layer. However, the biological characteristics of SRCC remain unclear. We aimed to clarify the pathological and genetic features of SRCC in H. pylori-uninfected patients. METHODS Seventeen H. pylori-uninfected patients with mucosal SRCCs were enrolled and their clinicopathological characteristics were compared with those of H. pylori-infected patients with mucosal SRCCs. Seven SRCCs without H. pylori-infected, including two invasive SRCCs, and seven H. pylori-infected SRCCs were subjected to a genetic analysis using next-generation sequencing. RESULTS H. pylori-uninfected patients with mucosal SRCCs revealed male dominancy and a significantly higher prevalence of smokers among them as compared with the H. pylori-infected patients with SRCC. A CDH1 mutation (frame shift indel) was detected in one H. pylori-uninfected cancer not only in the mucosal SRCC but also in the invasive portion. A TP53 mutation was detected in one SRCC without H. pylori-infected. In the control group, ARID1A and TP53 mutations were detected in one SRCC each. The C to A mutation, which is a characteristic smoking-induced mutation, was not found in any of the samples. CONCLUSIONS Some SRCCs in H. pylori-uninfected patients may have a malignant potential similar to that of SRCCs in H. pylori-infected patients. Smoking may not be the main carcinogenic factor for the development of SRCCs among the H. pylori-uninfected patients.
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Affiliation(s)
- Mariko Kiso
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Yuji Urabe
- Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Masanori Ito
- Department of General Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuhiko Masuda
- Department of Gastroenterology, Miyoshi Central Hospital, Hiroshima, Japan
| | - Tomoyuki Boda
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Takahiro Kotachi
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Kosaku Hata
- Department of Gastroenterology, Chugoku Rosai Hospital, Hiroshima, Japan
| | - Naoki Yorita
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Naoko Nagasaki
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Madina Abduwali
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Yuich Hiyama
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
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21
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The role of toll-like receptor 9 (TLR9) in Epstein-Barr virus-associated gastric cancer. CURRENT ISSUES IN PHARMACY AND MEDICAL SCIENCES 2020. [DOI: 10.2478/cipms-2020-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection. Toll-like receptors (TLRs) as major components of innate immune system are crucial in the development of inflammatory processes and carcinogenesis. The aim of our study was to evaluate tissue and serum level of TLR9 in EBV-positive and EBV-negative gastric cancer patients. The study involved 30 EBV(+) and 30 EBV(-) patients. EBV DNA was detected in fresh frozen tumor tissue. In serum samples TLR9 level, transforming growth factor β (TGFβ), interleukin 10 (IL-10) and antibodies against EBV were detected using ELISA tests. TLR9 level was also measured in homogenate of tumour tissue. TLR9 level was statistically lower in EBV(+) patients both in serum and tissue, with statistically higher level in tissue than in serum. Lower level of TLR9 was accompanied by higher level of Epstein-Barr virus capsid antigen (EBVCA), Epstein-Barr virus nuclear antigen (EBNA) and early antigen (EA). A lower level of TLR9 was detected in patients with poorly differentiated cancer (G3) and greater lymph nodes involvement (N3-N4). Lower level of TLR9 in patients with EA may point to TLR9 role in reactivation of EBV infection.
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22
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Niedźwiedzka-Rystwej P, Grywalska E, Hrynkiewicz R, Wołącewicz M, Becht R, Roliński J. The Double-Edged Sword Role of Viruses in Gastric Cancer. Cancers (Basel) 2020; 12:cancers12061680. [PMID: 32599870 PMCID: PMC7352989 DOI: 10.3390/cancers12061680] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/14/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
Due to its high morbidity and mortality, gastric cancer is a topic of a great concern throughout the world. Major ways of treatment are gastrectomy and chemotherapy, unfortunately they are not always successful. In a search for more efficient therapy strategies, viruses and their potential seem to be an important issue. On one hand, several oncogenic viruses have been noticed in the case of gastric cancer, making the positive treatment even more advantageous, but on the other, viruses exist with a potential therapeutic role in this malignancy.
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Affiliation(s)
- Paulina Niedźwiedzka-Rystwej
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
- Correspondence:
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
| | - Rafał Hrynkiewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Mikołaj Wołącewicz
- Institute of Biology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Poland; (R.H.); (M.W.)
| | - Rafał Becht
- Clinical Department of Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University of Szczecin, 70-204 Szczecin, Poland;
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; (E.G.); (J.R.)
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Küçük C, Wang J, Xiang Y, You H. Epigenetic aberrations in natural killer/T-cell lymphoma: diagnostic, prognostic and therapeutic implications. Ther Adv Med Oncol 2020; 12:1758835919900856. [PMID: 32127923 PMCID: PMC7036507 DOI: 10.1177/1758835919900856] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 12/19/2019] [Indexed: 12/11/2022] Open
Abstract
Natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that usually presents in the upper aerodigestive tract. This malignancy shows substantial geographic variability in incidence, and is characterized by Epstein-Barr virus (EBV) infections. Epigenetic aberrations may dysregulate the expression of genes involved in different hallmarks of cancer. A growing body of evidence underscores the importance of epigenetic aberrations in the pathogenesis of NKTCL. Promoter hypermethylation is a common epigenetic mechanism for the inactivation of tumour suppressor genes. Several epigenetically silenced tumour suppressor candidates (e.g. PRDM1, BIM) were identified in this aggressive cancer using locus-specific and genome-wide promoter methylation analyses. Importantly, genes involved in epigenetic modifications were identified to be mutated (e.g. KMT2D) or methylated (e.g. TET2) in NKTCL patients, which may contribute to pathogenesis through global alterations in chromatin states. Cancer-associated microRNAs, some of which are expressed by EBV, and long noncoding RNAs have been observed to be dysregulated in NKTCL. This review focuses on studies investigating epigenetic aberrations in NKTCL to bolster our overall understanding of the role of these abnormalities in disease pathobiology. We also discuss the potential of these epigenetic aberrations to improve diagnosis and prognosis as well as reveal novel targets of therapy for NKTCL.
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Affiliation(s)
- Can Küçük
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Junli Wang
- Department of Reproduction and Genetics, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Ying Xiang
- Division of Hematology and Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China
| | - Hua You
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Heng-Zhi-Gang Road, Yue Xiu District, Guangzhou 510095, China
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Yoon JH, Min K, Lee SK. Epstein-Barr Virus miR-BART17-5p Promotes Migration and Anchorage-Independent Growth by Targeting Kruppel-Like Factor 2 in Gastric Cancer. Microorganisms 2020; 8:microorganisms8020258. [PMID: 32075248 PMCID: PMC7074886 DOI: 10.3390/microorganisms8020258] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/12/2020] [Accepted: 02/13/2020] [Indexed: 12/24/2022] Open
Abstract
Epstein-Barr virus (EBV) infects more than 90% of the global population and is associated with a variety of tumors including nasopharyngeal carcinoma, Hodgkin lymphoma, natural killer/T lymphoma, and gastric carcinoma. In EBV-associated gastric cancer (EBVaGC), highly expressed EBV BamHI A rightward transcripts (BART) miRNAs may contribute to tumorigenesis with limited viral antigens. Despite previous studies on the targets of BART miRNAs, the functions of all 44 BART miRNAs have not been fully clarified. Here, we used RNA sequencing data from the Cancer Genome Atlas to find genes with decreased expression in EBVaGC. Furthermore, we used AGS cells infected with EBV to determine whether expression was reduced by BART miRNA. We showed that the expression of Kruppel-like factor 2 (KLF2) is lower in AGS-EBV cells than in the AGS control. Using bioinformatics analysis, four BART miRNAs were selected to check whether they suppress KLF2 expression. We found that only miR-BART17-5p directly down-regulated KLF2 and promoted gastric carcinoma cell migration and anchorage-independent growth. Our data suggest that KLF2 functions as a tumor suppressor in EBVaGC and that miR-BART17-5p may be a valuable target for effective EBVaGC treatment.
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Affiliation(s)
| | | | - Suk Kyeong Lee
- Correspondence: ; Tel.: +82-2-2258-7480; Fax: +82-504-201-2396
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Abstract
PURPOSE OF REVIEW The purpose of this article is to draw attention to the role of Epstein-Barr virus (EBV) virus in the pathogenesis of the primary Sjögren's syndrome. The article introduces the problem of consequences of EBV acute infection, and its reactivation, in association with the immune response modulation by the virus and with an increased risk of developing systemic autoimmune diseases and EBV-associated cancers. RECENT FINDINGS The knowledge about the mechanisms by which the virus may stay for years in a latent phase, unrecognized by the host response immune cells is constantly expanding. There are several mechanisms and theories about EBV influence on the autoimmune process in Sjogren's syndrome (pSS), including the similarity (molecular mimicry) between viral EBNA-2 protein and Ro-60 antigen or EBER-1 and EBER-2 viral proteins and La antigen. SUMMARY The influence of EBV infection on the development and course of pSS has been proven. It has also been established that both EBV and pSS result in the increased risk of tumor (especially lymphoma) development. In the light of these findings, new ways to manage EBV infections are being sought. Optimal methods for assessing EBV infection status are being devised. Research also aims at finding therapies, which target EBV through the inhibition of the autoimmune process and of viral activity. The present article is an attempt to discuss the most important phenomena and elements linking EBV infection to the primary Sjögren's syndrome.
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Affiliation(s)
- Maria Maślińska
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Early Arthritis Clinic, Spartanska1, Warsaw, Poland
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Abstract
Elevated plasma fibrinogen levels and tumor progression in patients with gastric cancer (GC) have been largely reported. However, distinct fibrinogen chains and domains have different effects on coagulation, inflammation, and angiogenesis. The aim of this study was to characterize fibrinogen β chain (FGB) in GC tissues. Retrospectively we analyzed the data of matched pairs of normal (N) and malignant tissues (T) of 28 consecutive patients with GC at diagnosis by combining one- and two-dimensional electrophoresis (1DE and 2DE) with immunoblotting and mass spectrometry together with two-dimensional difference in gel electrophoresis (2D-DIGE). 1DE showed bands of the intact FGB at 50 kDa and the cleaved forms containing the fragment D at ~37–40 kDa, which corresponded to 19 spots in 2DE. In particular, spot 402 at ~50 kDa and spots 526 and 548 at ~37 kDa were of interest by showing an increased expression in tumor tissues. A higher content of spot 402 was associated with stomach antrum, while spots 526 and 548 amounts correlated with corpus and high platelet count (>208 × 109/L). The quantification of FGB and cleaved products may help to further characterize the interconnections between GC and platelet/coagulation pathways.
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