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

EB 病毒相关胃癌的致癌作用。

基本信息

批准号：
18390110
负责人：
FUKAYAMA Masashi
金额：
$ 10.7万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390110/
关键词：
EBV-associated gastric carcinoma Epstein-Barr virus gastric carcinoma infectious agent and host interaction DNA methylation promoter carcinogenesis gastric carcinoma cell line

项目摘要

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.

表型：Epstein-Barr病毒（EBV）相关的胃癌（GC）在表型分类中被归类为NULL或胃类型，这是由粘蛋白分子和CD10的表达模式确定的。事实表明，EBV感染的靶标是胃皮细胞的干细胞。样本异常：在肿瘤抑制基因（TSG）启动子区域中CPG重复剂的甲基化甲基化，通过TSG的扭转抑制来促进癌症的发育。在许多TSG中，在高频下具有这种表观遗传异常的癌称为CpG岛甲基表型高（CIMP-H）。 EBV相关的GC被证明是CIMP-H GC的典型例子，但与EBV阴性CIMP-H GC相比，它显示出更多的甲基化基因。此外，在EBV相关的GC中特异性甲基化了TSG的P73基因。当比较p16中DNA甲基化的频率，p14和p73基因之间的非肿瘤性胃粘膜和早期胃癌之间的频率相似，这两者都相似，这表明DNA-甲基化在上皮细胞中沿EBV的感染发生DNA-甲基化。 - 感染的GC细胞系：对凋亡的抗性是与EBV相关GC的特征之一。它被检索为对血清缺乏诱导的GC细胞系的抗凋亡，并感染具有新霉素耐药基因的重组EBV。使用这些细胞系，我们证明了病毒潜在的蛋白LMP2A，通过激活NFKB途径上调了细胞存活基因。转基因小鼠：转基因小鼠是用H^+ K^+ ATPase启动子和EBV启动子和EBV laTENTENS构建的转基因小鼠基因。 LMP2A或EBNA1在胃皮细胞中实现特定表达。在转基因小鼠的胃中证实了EBV贴基因的表达。预计实验模型是对与EBV相关GC的发展进行详细分析。