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

表型：EB病毒相关性胃癌(GC)在表型分类中被归类为空型或胃型，这是由粘蛋白分子和CD10的表达模式决定的。表观遗传学异常：肿瘤抑制基因(TSG)启动子区CpG重复序列的甲基化通过TSG的转录抑制而促进肿瘤的发生。在许多TSG中出现这种表观遗传学异常的癌被称为CpG岛甲基化表型高(CIMP-H)。EBV相关性GC是CIMP-H GC的典型代表，但其甲基化基因明显多于EBV阴性的CIMP-H GC。此外，p73基因作为TSG的一种，在EBV相关的GC中被特异性甲基化。比较非肿瘤性胃黏膜和早期胃癌组织中p16、p14和p73基因的甲基化频率，两者的甲基化频率相似，提示DNA甲基化发生在上皮细胞中的EBV感染过程中。EBV感染的GC细胞株：抗凋亡是EBV相关GC的特征之一。在携带新霉素抗性基因的重组EBV感染的GC细胞系中，获得了对血清剥夺诱导的细胞凋亡的抗性。利用这些细胞系，我们证明了病毒潜伏蛋白LMP2A通过激活NFkB途径上调了细胞中的Survivin基因。转基因小鼠：构建了H^+K^+ATPase启动子和EBV潜伏基因的转基因小鼠。LMP2A或EBNA1实现在胃上皮细胞中的特异性表达。EBV潜伏基因在转基因小鼠的胃中得到了表达。该实验模型有望用于详细分析EBV相关GC的发展。

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.