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      Epstein-Barr Virus (EBV)-associated Gastric Carcinoma

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          Abstract

          The ubiquitous Epstein-Barr virus (EBV) is associated with several human tumors, which include lymphoid and epithelial malignancies. It is known that EBV persistently infects the memory B cell pool of healthy individuals by activating growth and survival signaling pathways that can contribute to B cell lymphomagenesis. Although the monoclonal proliferation of EBV-infected cells can be observed in epithelial tumors, such as nasopharyngeal carcinoma and EBV-associated gastric carcinoma, the precise role of EBV in the carcinogenic progress is not fully understood. This review features characteristics and current understanding of EBV-associated gastric carcinoma. EBV-associated gastric carcinoma comprises almost 10% of all gastric carcinoma cases and expresses restricted EBV latent genes (Latency I). Firstly, definition, epidemiology, and clinical features are discussed. Then, the route of infection and carcinogenic role of viral genes are presented. Of particular interest, the association with frequent genomic CpG methylation and role of miRNA for carcinogenesis are topically discussed. Finally, the possibility of therapies targeting EBV-associated gastric carcinoma is proposed.

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          The history of cancer epigenetics.

          Andrew Feinberg, Benjamin Tycko (2004)
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            Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice.

            Stefan Costinean, Nicola Zanesi, Yuri Pekarsky … (2006)
            MicroRNAs (miRNAs) represent a newly discovered class of posttranscriptional regulatory noncoding small RNAs that bind to targeted mRNAs and either block their translation or initiate their degradation. miRNA profiling of hematopoietic lineages in humans and mice showed that some miRNAs are differentially expressed during hematopoietic development, suggesting a role in hematopoietic cell differentiation. In addition, recent studies suggest the involvement of miRNAs in the initiation and progression of cancer. miR155 and BIC, its host gene, have been reported to accumulate in human B cell lymphomas, especially in diffuse large B cell lymphomas, Hodgkin lymphomas, and certain types of Burkitt lymphomas. Here, we show that E(mu)-mmu-miR155 transgenic mice exhibit initially a preleukemic pre-B cell proliferation evident in spleen and bone marrow, followed by frank B cell malignancy. These findings indicate that the role of miR155 is to induce polyclonal expansion, favoring the capture of secondary genetic changes for full transformation.
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              Causal relationship between the loss of RUNX3 expression and gastric cancer.

              Qing-Lin Li, Kosei Ito, Chohei Sakakura … (2002)
              Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Viruses
                Journal ID (iso-abbrev): Viruses
                Journal ID (publisher-id): viruses
                Title: Viruses
                Publisher: MDPI
                ISSN (Electronic): 1999-4915
                Publication date (Electronic): 29 November 2012
                Publication date Collection: December 2012
                Volume: 4
                Issue: 12
                Pages: 3420-3439
                Affiliations
                [1 ]Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan; Email: iizasah@ 123456igm.hokudai.ac.jp
                [2 ]Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6, Kita-ku, Sapporo 060-0812, Japan; Email: nanboa@ 123456pharm.hokudai.ac.jp
                [3 ]Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami-Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan; Email: junnis@ 123456yamaguchi-u.ac.jp
                [4 ]Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan; Email: jinushi@ 123456igm.hokudai.ac.jp (J.M.); hironori@ 123456igm.hokudai.ac.jp (H.Y.)
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ] Author to whom correspondence should be addressed; Email: hironori@ 123456igm.hokudai.ac.jp ; Tel.: +81-11-706-6073; Fax: +81-11-706-6071.
                Article
                Publisher ID: viruses-04-03420
                DOI: 10.3390/v4123420
                PMC ID: 3528272
                PubMed ID: 23342366
                SO-VID: 71c93910-2882-4835-83aa-7a25b678cd15
                Copyright © © 2012 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 22 October 2012
                Date revision received : 22 November 2012
                Date accepted : 26 November 2012
                Categories
                Subject: Review

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: mirna,methylation,epithelial,ebv,cd21,ebv-associated gastric carcinoma,carcinogenesis
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: mirna, methylation, epithelial, ebv, cd21, ebv-associated gastric carcinoma, carcinogenesis

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