C型凝集素样受体2通过β-catenin/IL-8通路调控胃部炎症及胃癌发生的功能机制研究

Gastric cancer is the second most common cancer in China, and accounts for nearly 42% of the annual new cases worldwide. C-type lectin-like receptor 2 (CLEC2) is a member of the C-type lectin family, and belongs to type II transmembrane receptor. Our previous study has identified that the CLEC2 was reduced in gastric cancer tissues compared with non-tumor mucosa and correlated with aggravated tumor invasion, lymph node metastasis ,advanced TNM stage and reduced overall survival (Gastroenterology, 2016). We also found that CLEC2could modulate the expression of Interleukin 8 (IL-8) in gastric epithelia cells. IL-8 was widely believed to a possible factor that affected gastritis and gastric cancer. In consequence, we speculated that CLEC2 might contribute to an intense inflammable response caused by Helicobacter pylori (HP) infection in the precancerous diseases in stomach. However, the functional significance of CLEC2 in multistep cascade model for the development of gastric cancer has not been further investigated. This project proposal for grant application is designed to elucidate whether altered expression of CLEC2 is related to the occurrence of precancerous diseases and tumor in stomach. We will also identify the functional significance and molecular mechanism of CLEC2 in regulating the inflammation and carcinogenesis of gastric tissues via β-catenin/IL-8 pathway and will establish a model of molecular regulation and therapeutic intervention, which paves the way to clinical investigation and drug discovery to treat gastric precancerous diseases.

胃癌在我国的发病率居所有恶性肿瘤的第二位，每年的新发病例占全世界的42%。C型凝集素样受体2（CLEC2）是C型凝集素家族中的一员，属于II型跨膜蛋白。项目申请人前期研究发现CLEC2在胃癌中较癌旁低表达，并且其低表达与胃癌的侵袭、不良的预后相关（Gastroenterology, 2016）。研究还发现正常胃上皮细胞中CLEC2能够调节IL-8的表达，而IL-8被认为是导致胃部炎症及胃癌的因素，因此我们认为CLEC2可能参与了胃癌前疾病的炎症反应，尤其是幽门螺旋杆菌感染导致的慢性炎症。然而其在胃癌前疾病中的功能意义尚未进一步研究。本申请项目拟在前期实验基础上，探讨CLEC2的表达与胃癌前疾病和胃癌发生的关系，同时探讨CLEC2通过β-catenin/IL-8通路调控胃部炎症与胃癌发生的功能意义及分子机制，并在此基础上建立其参与胃癌发生的分子调控模型，为治疗胃癌前疾病的药物的开发奠定基础。

本项目从可能影响胃癌发生发展及预后的关键分子及其作用机制的角度出发，分别研究了C型凝集素样受体2(CLEC2）在调控胃部炎症及胃癌发生的功能机制研究；IRTKS在促进胃癌进展中的作用机制及与预后的关系；G3BP1与YWHAZ相互作用调控胃癌化疗耐药及预测胃癌患者术后化疗获益。研究发现CLEC2的表达下调从胃部炎症就开始，但在异型增生的阶段最为显著，且下调后能够促进炎症因子IL-8的表达及β-catenin的活化。进一步研究发现HP感染同样能够引起CLEC2的下调，促进β-catenin的活化和IL-8表达的升高，并揭示CLEC2通过β-catenin/IL-8通路调控胃部炎症及胃癌发生。在胃癌中IRTKS表达上调，且与野生型p53患者的不良预后相关。进一步研究发现IRTKS通过负调控p53促进胃癌细胞的增殖，且以p53依赖的方式抑制肿瘤发生。体内实验发现IRTKS下调可促进杂合子p53小鼠胚胎成纤维细胞(MEFs)的细胞周期阻滞和凋亡，而IRTKS可促进MEFs细胞和胃癌细胞中p53的泛素化降解。在胃癌中G3BP1高表达与接受辅助化疗的胃癌患者生存期差相关，且G3BP1在体内外均能增强胃癌对化疗药物的耐药性。进一步研究发现G3BP1可以通过调节应激颗粒的形成，抑制细胞凋亡和Bax的表达。此外，G3BP1与YWHAZ相互作用，可通过调节凋亡调节因子Bax的细胞定位，最终导致化疗耐药。以上从胃部炎症到胃癌的发生，胃癌的进展，以及化疗耐药的关键分子机制研究进一步揭示了胃癌发生、发展和治疗中的关键分子，可作为胃癌诊疗中潜在的治疗靶点。