Carcinogenesis of EB virus-associated gastric carcinoma. Mutual DNA-methylation of host and infective agent.

点击翻译按钮获取中文摘要

Phenotype : Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) was classified as null or gastric type in the phenotype classification, which was determined by the expression pattern of mucin molecules and CD10. The fact suggests that the target of EBV-infection is the stem cell of gastric epithelium.Epigenetic Abnormality: Methylation of cytocine of the CpG repeats in promoter region of tumor suppressor genes (TSG) facilitates the cancer development through trascription repression of TSG. The carcinomas with such epigenetic abnormalities at high frequencies in many TSG are called as CpG island methylator phenotype high (CIMP-H). EBV-associated GC was demonstrated as a typical example of CIMP-H GC, but it showed much more methylated genes than EBV-negative CIMP-H GC. Furthermore, p73 gene one of TSG, was specifically methylated in EBV-associated GC. When the frequencies of DNA methylation in p16, p14, and p73 genes were compared between the non-neoplastic gastric mucosa and early gastric carcinomas, both were similarly low, suggesting that DNA-methylation occurs along the infection of EBV in the epithelial cells.EBV-infected GC cell lines: Resistance to apoptosis is one of characteristics to EBV-associated GC. It was retrieved as resistance to serum deprivation-induced apoptosis in GC cell lines with infection of recombinant EBV harboring Neomycin resistance gene. Using these cell lines, we demonstrated that viral latent protein, LMP2A, up-regulates cellular survivin gene through activation of NFkB pathway.Transgenic mouse: The transgenic mouse was generated with the construct of H^+K^+ ATPase promoter and EBV-latent genes. LMP2A or EBNA1 to achieve the specific expression in the gastric epithelial cells. The expression of EBV-latent genes was confirmed in the stomach of the transgenic mice. The experimental model is anticipated for the detailed analysis of the development of EBV-associated GC.