Epstein-Barr virus and gastric carcinoma.
Epstein-Barr virus (EBV) has been accepted as an infective agent causing gastric carcinoma (GC). Epstein-Barr virus-associated GC, comprising nearly 10% of all cases of GC, is the monoclonal growth of EBV-infected epithelial cells, which express several EBV-latent genes (latency I program). Sequential events in the gastric mucosa could be traced from EBV infection of the pit cells to fully developed carcinomas by EBV encoded small RNA (EBER)-in situ hybridization. The histological features of the carcinoma consist of a lace pattern of carcinoma cells within the mucosa and the dense infiltration of lymphocytes and macrophages at the invasive site, which might be due to cytokines produced by neoplastic cells. The primary molecular abnormality in EBV-associated GC is global and non-random CpG island methylation in the promoter region of many cancer-related genes. The experimental system of recombinant EBV infection using GC cell lines demonstrated that viral latent membrane protein 2A (LMP2A) is responsible for the promotion of DNA methylation. LMP2A up-regulates cellular DNMT1 through the phosphorylation of STAT3, causing CpG methylation of a tumor suppressor gene, PTEN. DNA methylation in EBV-infected stomach cells may be due to overdrive of the cellular defense against foreign DNA, which eventually leads to the development of EBV-associated GC.
Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. mfukayama-tky@umin.ac.jp
Masashi
M
Fukayama
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000821:virology*; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D017403:In Situ Hybridization; D008745:Methylation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D012367:RNA, Viral / Q000032:analysis; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D012334:RNA, Neoplasm; D012367:RNA, Viral; D014763:Viral Matrix Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human