aPKCι/MCP-1介导癌细胞-TAMs正反馈环路抑制癌细胞铁死亡促进胆囊癌化疗耐药的机制研究

肿瘤免疫微环境与癌细胞的化疗耐药性密切相关。申请人近期发现：过表达aPKCι的胆囊癌细胞可诱导M2型TAMs活化；M2型TAMs促进aPKCι介导的癌细胞铁死亡抵抗，增强细胞对吉西他滨的耐药性；aPKCι可能介导胆囊癌细胞分泌MCP-1诱导M2型TAMs活化，M2型TAMs又能促进癌细胞分泌MCP-1。我们据此推测：aPKCι/MCP-1介导癌细胞与TAMs之间形成正反馈环路，通过抑制癌细胞铁死亡促进胆囊癌的化疗耐药性。本项目拟开展以下研究：（1）明确aPKCι调控胆囊癌细胞分泌MCP-1诱导TAMs活化的生物学过程；（2）阐明aPKCι/MCP-1介导癌细胞-TAMs形成正反馈环路抑制胆囊癌细胞铁死亡的分子机制；（3）证实aPKCι/MCP-1调控癌细胞-TAMs正反馈环路抑制癌细胞铁死亡对胆囊癌化疗耐药的影响。本项目将从新的角度阐述胆囊癌化疗耐药的分子机制，为胆囊癌的治疗提供新思路。

The tumor immune microenvironment is closely related to the chemoresistance of cancer cells. Our previous study found that overexpression of aPKCι promoted gallbladder cancer cells to recruit and induce the activation of M2-like tumor-associated macrophages (TAMs); M2-like TAMs in turn enhanced aPKCι-mediated ferroptosis resistance and gemcitabine-resistant in gallbladder cancer; aPKCι may activate M2-like TAMs by regulating the secretion of MCP-1 in gallbladder cancer cells, while M2-like TAMs in turn increased the secretion of MCP-1 from gallbladder cancer cells. Based on the above results, we speculate that aPKCι/MCP-1 may mediate a positive feedback loop between cancer cells and TAMs, which promotes chemoresistance of gallbladder cancer cells by inhibiting ferroptosis. To this end, the project is planned to: (1) study how aPKCι regulates the secretion of MCP-1 from gallbladder cancer cells to induce the activation of TAMs; (2) explore the molecular mechanism that aPKCι/MCP-1 mediates the cancer cells-TAMs positive feedback loop to inhibit ferroptosis in gallbladder cancer cells; (3) analyze the influence of the cancer cells-TAMs positive feedback loop regulating by aPKCι/MCP-1 on the chemoresistance of gallbladder cancer cells. This project is designed to elaborate the molecular mechanism of the chemotherapy resistance of gallbladder cancer in a new perspective. It may provide new ideas for the treatment of gallbladder cancer.