幽门螺杆菌CagA蛋白在胃癌代谢重编程中的作用及调控机制

细胞代谢重编程是肿瘤发生发展的中心环节，而能量代谢改变是其始动因素和核心内容。前期研究发现幽门螺杆菌（H.pylori）的CagA蛋白能上调胃癌组织和细胞中能量代谢酶：乳酸脱氢酶-A（LDH-A）、二氢硫辛酰胺脱氢酶(DLD)及ATP合酶α亚基的表达，分别参与糖酵解、有氧氧化和氧化磷酸化三个重要的能量代谢。我们推测H.pylori感染胃黏膜后，将其CagA注入胃上皮细胞，通过上调能量代谢酶基因的表达，引起能量代谢改变，驱动细胞发生代谢重编程，促进胃癌的生长和转移。本项目拟在已构建的高表达cagA的胃癌细胞模型中沉默这3个基因，检测能量代谢指标的变化及细胞在体内、外的致癌能力，研究CagA调控能量代谢的关键酶，探索能量代谢改变后细胞的致癌能力；用代谢组学构建CagA诱导的代谢重编程的模式，在胃癌组织中验证参与重编程的代谢酶，从代谢重编程的角度揭示H.pylori引起胃癌的分子机制。

Cell metabolic reprogramming is a key step in the development and progression of tumor. The alteration of energy metabolism is an important initiation factor for cell metabolic reprogramming. We found that Helicobacter pylori (H.pylori) CagA upregulated the expression of lactate dehydrogenase-A (LDH-A), dihydrolipoamide dehydrogenase (DLD) and ATP synthase alpha subunit, which participate in glycolysis, aerobic oxidation and oxidative phosphorylation, respectively. Therefore, we speculate that CagA promotes cell growth and metastasis of gastric cancer by inducing cell metabolic reprogramming through upregulating expression of LDH-A, DLD and ATP synthase alpha subunit. In this study, these three genes will be silenced in cagA-overexpressed gastric cancer cell lines, and the changes of energy metabolism　and tumor formation ability in vitro and in vivo are measured to study the alterations of energy metabolism and its key enzymes induced by CagA and potential of this alteration to regulate cell transformation. Metabonomics information will be used to generate cell models of metabolic reprogramming by CagA, and the enzymes selected from altered metabolic enzymes will be validated in human gastric cancer tissues. This study will reveal molecular mechanism of metabolic reprogramming in gastric cancer induced by CagA.