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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）相关胃癌（GC）在表型分类中分为null型或胃型，由粘蛋白分子和CD10的表达模式决定。这表明ebv感染的目标是胃上皮干细胞。表观遗传异常：肿瘤抑制基因（TSG）启动子区域CpG重复序列的细胞素甲基化通过TSG的转录抑制促进癌症的发生。在许多TSG中具有这种高频率表观遗传异常的癌被称为CpG岛甲基化表型高（CIMP-H）。ebv相关GC是典型的CIMP-H GC，但其甲基化基因比ebv阴性CIMP-H GC多得多。此外，TSG基因之一的p73基因在ebv相关GC中特异性甲基化。当比较非肿瘤性胃粘膜和早期胃癌中p16、p14和p73基因的DNA甲基化频率时，两者都相似地低，表明DNA甲基化发生在上皮细胞中EBV感染的过程中。ebv感染的GC细胞系：抗凋亡是ebv相关GC的特征之一。结果表明，含新霉素耐药基因的重组EBV感染GC细胞株，对血清剥夺诱导的细胞凋亡具有抗性。利用这些细胞系，我们证明了病毒潜伏蛋白LMP2A通过激活NFkB途径上调细胞survivin基因。转基因小鼠：用H^+K^+ atp酶启动子和ebv潜伏基因构建转基因小鼠。LMP2A或EBNA1在胃上皮细胞中实现特异性表达。证实了ebv潜伏基因在转基因小鼠胃内的表达。该实验模型可用于详细分析ebv相关气相色谱的发展。