胃癌是我国乃至世界范围内高发及高死亡率的恶性肿瘤，PI3K/Akt信号高激活促进其恶性进展。前期发现，肌醇5-磷酸酶SHIP2作为抑癌因子，在胃癌表达下调激活PI3K/Akt信号促进胃癌的发生发展。质谱和酵母双杂交实验共同鉴定的SHIP2互作蛋白prohibitin-2（PHB2），可促进SHIP2蛋白降解；而PHB2在胃癌细胞表达上调，促进其增殖和迁移侵袭。我们推断：PHB2通过影响SHIP2蛋白稳定性介导Akt活化促进胃癌进展和转移。本项目拟建立PHB2 shRNA敲低和过表达胃癌细胞系，通过病理组织分析以及动物实验明确PHB2可作为预测胃癌进程及预后的指标；阐明胃癌细胞中PHB2上调促进SHIP2降解，活化Akt继而影响下游信号分子表达的分子机制；探索靶向PHB2联合Akt抑制剂对胃癌的疗效。本项目将较清晰阐明PHB2在胃癌进展和转移中的分子机制，为寻求胃癌潜在治疗靶点提供实验依据。

Gastric cancer is one of the most malignant tumors with high morbidity and mortality in China and worldwide. The PI3K/Akt signaling pathway is highly activated in gastric cancer cells, which promotes tumor growth and metastasis of gastric cancer. Our previous data has demonstrated that，as an important tumor suppressor, the reduced expression of the inositol polyphosphate 5-phosphatase SHIP2 in gastric cancer promotes cell growth, proliferation, migration and invasion of gastric cancer through activation of PI3K/Akt signaling pathway. Further investigation has shown that prohibitin-2（PHB2）which is screened by mass spectrometry and yeast two-hybrid system, physically interacts with SHIP2 and leads to the degradation of SHIP2 protein. We have also found that PHB2 is up-regulated in gastric cancer cell lines, which promotes proliferation, migration and invasion of gastric cancer cells. Therefore, we propose the hypothesis that PHB2 promotes the malignant progression and metastasis of gastric cancer through down-regulation of SHIP2-mediated activation of Akt. . The specific aims of this project are: to determine whether PHB2 up-regulation is associated with malignant progression of gastric cancer and is predictive of poor patient prognosis; to clarify the mechanisms responsible for up-regulation of PHB2 and the mechanisms underlying PHB2-mediated SHIP2 degradation, and subsequent activation of Akt; to identify the effect of co-targeting PHB2 and Akt as a novel combined approach in the treatment of gastric cancer. . Taken together, this study will provide strong evidence of the oncogenic roles of PHB2, as well as the new idea for the mechanisms of progression and metastasis in gastric cancer and a molecular target for therapeutic intervention in gastric cancer.