胃癌细胞内的促生存信号通路往往处于高激活状态，影响其治疗效果，其中针对PI3K/Akt信号通路的研究越来越多引起人们的关注。SHIP2作为多磷酸肌醇5-磷酸酶家族一员，能通过水解胞内第二信使PIP3而下调Akt的活性，从而抑制肿瘤生长。我们前期研究发现SHIP2在胃癌细胞中的表达下调与组蛋白的低乙酰化水平相关，并且高表达SHIP2降低了胃癌细胞的生存和增殖。本项目将在此基础上，进一步明确SHIP2在胃癌发生和发展中的作用，阐明其通过负调控PI3K/Akt信号通路以抑制肿瘤生长的作用机制。同时探讨在胃癌细胞中SHIP2和PTEN发挥作用的方式和相互关系，并初步揭示组蛋白去乙酰化调控SHIP2在胃癌中低表达的分子机制。本研究不仅可为研究胃癌的发生发展机制提供新的思路，同时也为胃癌的靶向治疗提供新的分子靶点。而对下调SHIP2表达的HDAC的鉴定将有益于发展更特异的HDAC抑制剂抑制肿瘤生长。

Since pro-survival signaling pathway is highly activated in gastric cancer cells, the therapeutic effect remains weak and the research on pro-survival signaling pathway, especially PI3K/Akt signaling pathway, attracts more and more attention. SHIP2, a member of inositol polyphosphate 5-phosphatases, can terminate the activation of Akt through hydrolyzing the second message PIP3. Our previous data has demonstrated that downregulation of SHIP2 is associated with histone hypoacetylation in gastric cancer cells, and overexpression of SHIP2 decreases survival and proliferation of gastric cancer cells. Based on that, we will further investigate the role of SHIP2 in carcinogenesis and progression of gastric cancer, and clarify the mechanism of inhibiting tumor growth through negative regulation of PI3K/Akt signaling pathway. Moreover, we will examine the mode and interaction between SHIP2 and PTEN in gastric cancer cells, and preliminarily explore the molecular mechanism of downregulation of SHIP2 regulated by histone deacetylation. Taken together, this research provides not only a new idea for the mechanism of carcinogenesis and progression in gastric cancer, but also a new molecular target for gastric-cancer-targeted therapy. In addition, the identification of HDAC that downregulates SHIP2 expression will be helpful to develop more specific HDAC inhibitor that can inhibit tumor growth.