Hippo信号通路基因甲基化与幽门螺杆菌相关胃癌发病及预后的关系

Gastric cancer (GC) is a complex disease. Multiple factors, including genetic, environmental and Helicobacter pylori (H.pylori) infectious agents, lead to the GC carcinogenesis and tumor progression. Hippo, as a new molecular regulation pathway, was found to be involved in the development and metastasis of GC. Unfortunately, The data are limited on the relative contribution in population until now. H.pylori infection is strongly associated with GC, but only a minority of infected individuals ever develop it, which suggests only H.pylori infection with carcinogenic potency is a key factor in GC. But now the researches on carcinogenic factor of H.pylori are largely limited to the comparison among different pathogenic strains. In addition, it has been suggested that H.pylori infection and host genetic characteristics could influence each other, and environmental factors might also increase the risk of H.pylori infection and affect the levels of DNA methylation. Accordingly, in the present study, we aim to detect the aberrant promoter CpG islands methylation of Hippo pathway genes as well as the level of virulence proteins related to H.pylori infection in our established GC case-control study population. Combine these above results with environmental factors which may be associated with H.pylori infection or GC development, and regularly follow-up informations of the GC patients, we would explore the independent and interaction effect of these factors on the carcinogenesis and prognosis of GC systematically and comprehensively. Moreover, these results may offer indicators for early prevention, individual intervention and prognosis improvement of GC in population.

胃癌的发生发展是环境、遗传和幽门螺杆菌（H.pylori）感染共同作用的结果。Hippo是新发现的分子调控通路，研究表明其参与胃癌的发生、发展和转移，但人群研究非常有限。H.pylori是胃癌公认的致病因子，然而感染后仅极少部分个体致癌，因此H.pylori感染并非致癌因素，有致癌毒力的H.pylori感染才是，但目前此领域研究基本限于病原学菌株之间的比较。此外，H.pylori感染与宿主遗传特征会相互影响，特定的环境因素也会增加H.pylori感染危险及影响DNA甲基化水平。故此，本项目拟在我们已建立的病例对照人群中，既检测Hippo通路基因启动子区CpG岛甲基化情况，又检测H.pyloi致癌相关毒力蛋白水平，同时调查与胃癌及H.pylori感染相关的环境因素，并对胃癌患者进行定期随访，综合分析这些因素单独和交互作用对胃癌发病和预后的影响，进而为胃癌的个体化防治、改善预后提供指标。

我国是胃癌高发国家，目前尚缺乏有效的生物标志物对其做出早期诊断。本研究应用病例对照研究方法，探索外周血中Hippo信号通路基因及相关基因甲基化水平与胃癌发病及预后的关系，评价H. pylori相关毒力蛋白生物标志物在胃癌血清学筛查中的应用价值。研究发现FAT4、SOX11、KIBRA、EPHA5、DLEC1、WT1和SOCS3等基因甲基化与胃癌发病风险显著相关，毒力蛋白KatA、AhpC、FliD和CagA与胃癌发病风险显著相关并具有较高筛查价值。本研究还利用体外细胞实验探索Hippo信号通路相关信号分子在胃癌发生发展中的作用。此外，本课题组通过目标区域捕获甲基化测序的方法进行胃癌相关差异甲基化基因的初步筛选，为寻找胃癌相关的生物标志物提供新的线索。