候选肿瘤抑制基因REC8在EB病毒相关胃癌中的功能研究及潜在临床应用价值

Gastric cancer is one of the most common cancers in China. Epstein-Barr virus (EBV) was discovered in gastric cancer since 1990s. However, the underlying mechanism and the pathogenesis of EBV in gastric cancer are still unclear. Increasing evidences showed significantly higher frequencies of promoter CpG methylation of tumor suppressor genes in EBV-associated gastric cancer than in EBV-negative gastric cancer. However, the effect of EBV infection on the genome-wide aberrant DNA methylation remains unclear. We aim to profile the genome-wide EBV-associated hypermethylation in EBV-infected cells, to identify EBV-associated methylated genes and to elucidate their function in gastric carcinogenesis. In our previous study, we used a high throughput technique, called methylated DNA immunoprecipitation coupled with hybridization on high-resolution microarray (MeDIP-chip), for a genome-wide evaluation of EBV-related methylation genes in gastric cancer and identify a candidate tumor suppressor gene-REC8 gene with methylation fold change 23.5. We found that the expression of REC8 will be significantly restored after demethylation treatment. In this study, we will focus on the following issues on the former basic research. Firstly, we will evaluate both the methylation and the mRNA expression of REC8 in gastric cancer cell lines and explore the correlation between them. Moreover, we will investigate the biological function of REC8 in gastric cancer cell lines by using gain and loss approaches to observe the effect of REC8 in vivo and in vitro. Secondly, we will explore the putative signal pathway of REC8 to elucidate its molecular mechanism. Finally, we will assess REC8 methylaiton in gastric cancer samples and reveal its clinicopathological significance.

胃癌是我国发病率、死亡率均位居前三位的癌症，近年发现胃癌组织中可检测到EB病毒(EBV)，但EB病毒相关胃癌(EBVaGC)的发病机制尚不明确。研究发现EBVaGC存在一个或多个肿瘤相关基因的甲基化，从全基因组的角度研究EBV引起的宿主细胞甲基化图谱的变化，已成为研究EBVaGC发病机制的新视角。前期我们采用甲基化DNA免疫共沉淀-芯片技术，发现候选肿瘤抑制基因-REC8在EBV感染的胃癌细胞中呈现高甲基化，通过药物去甲基化可导致其重新表达。本课题拟在原有基础上开展以下研究：1）研究EBVaGC中REC8甲基化的改变，及REC8作为肿瘤抑制因子在EBVaGC发展中的生物学功能；2）阐明REC8在EBVaGC中抑癌作用的信号通路；3）揭示REC8在EBVaGC的临床病理学意义，探讨甲基化的REC8作为EBVaGC判断预后的分子生物学标志物的临床应用价值。