幽门螺杆菌通过CagA介导β-catenin转位在胃癌复发中的作用及其分子机制研究

Hp感染与胃癌复发密切相关.我们前期发现CagA+Hp通过促β-cat核转位上调Nanog和Oct4,增强胃癌细胞干性特性,但β-cat核转位的前提——β-cat从胞膜上释放的机制不清.前期预实验发现CagA+Hp可诱导CD44-胃癌细胞表达干性标志CD44,提示CagA+Hp可能诱导终末期胃癌细胞重编程而获得胃癌干细胞样特性.结合文献及前期工作,我们推测Hp通过CagA和p120结合,使p120构象改变并从E-cad上脱落,暴露E-cad胞内段酪氨酸酶磷酸化位点,启动E-cad胞内段泛素化降解，使β-cat从E-cad上释放, β-cat继而发生核转位,诱导终末期胃癌细胞重编程为胃癌干样细胞,导致胃癌复发.本课题拟采用GST pull-down,IF等实验,阐明CagA+Hp促β-cat转位的分子机制及其在胃癌细胞重编程中的作用,为胃癌术后根除Hp提供理论依据,为预防胃癌复发提供新靶点.

H.pylori infection is closely associated with the recurrence of gastric cancer. We previously found that CagA-positve H.pylori upregulates Nanog and Oct4 via β-catenin nuclear translocation to promote cancer stem cell-like properties in gastric cancer. However, as the premise of β-catenin nuclear translocation, the mechanism of CagA-positve H.pylori-mediated the release of β-catenin from the membrane is unclear. Our previous experiments found that CagA-positve H.pylori induces CD44-negative gastric cancer cells re-expression of gastric cancer stem cell marker CD44, which imply CagA-positve H.pylori could induce reprogramming of gastric cancer cells to obtain gastric cancer stem cell-like properties. Based on literatures and our previous work, we hypothesize that H.pylori CagA directly binds with p120, leading to p120 structural change and release from E-cadherin. The release of p120 exposes E-cadherin intracellular tyrosinase phosphorylation sites and initiates E-cadherin ubiquitin degradation pathway, resulting in the release of β-catenin from the E-cadherin and the nuclear translocation of β-catenin. β-catenin nuclear translocation induces gastric cancer cells reprogramming to obtain gastric cancer stem cell-like properties, resulting in recurrence of gastric cancer. This study intends to use GST pull-down and immunofluorescence et al. to clarify the molecular mechanism of CagA-positve H.pylori-induced β-catenin translocation and its role in CagA-positve H.pylori-induced gastric cancer cells reprogramming. The aim is to provide a theoretical basis for Hp eradication in gastric cancer and provide a new target for preventing recurrence of gastric cancer.