炎症应激和代谢应激是结肠癌发病的重要因素，而这两种因素又参与调控结肠癌干细胞干性的维持。自噬是清除细胞内受损细胞器、错误折叠蛋白和其它生物大分子的重要途径，是机体对抗炎症和应激反应的重要机制。本项目前期工作证实，应激蛋白TRIB3可抑制肿瘤细胞自噬活性，抑制几个关键的促肿瘤蛋白降解，诱导肿瘤发生、发展。同时，我们发现TRIB3参与调控了结肠癌细胞代谢重编程和细胞缺氧，敲低结肠癌细胞TRIB3可抑制结肠癌细胞的生长和转移。基于上述工作基础，本项目将使用临床样本、转基因动物及细胞模型拟寻找结肠癌发病中TRIB3所抑制自噬与结肠癌代谢重编程、肿瘤免疫微环境、结肠癌干细胞干性之间的联系。我们还将使用本项目前期所筛选到的活化细胞自噬的先导化合物作为分子探针，分析其抗结肠癌的作用和机制。本研究揭示的结肠癌分子细胞发病机制将为结肠癌的防治和新药研发提供理论支持和思路。

Inflammatory and metabolic stresses are associated with increased risk of colon cancer development and progression through supporting the stemness of colon cancer stem cells. Autophagy is a critical intracellular process for the clearance of pathogens, injured/aged organelles, misfolded proteins and other biomacromolecules as considering a cytoprotective mechanism against inflammatory and metabolic stresses. In preliminary studies, we have fund that TRIB3, a stress response protein, can suppress autophagy in cancer cells, which results in the accumulation of a lot of cancer-related proteins and promotes cancer progression. Also, we have found that TRIB3 participates into the metabolic reprogramming and hypoxia of colon cancer cells, and knockdown TRIB3 prevents colon cancer cell proliferation and metastasis. With these findings, we propose investigate the potential roles and mechanisms of TRIB3-suppressed autophagy in the regulation of colon cancer metabolic reprogramming, cancer immune microenvironment and the stemness of colon cancer stem cells. We also want to determine the potential therapeutic effects by using an autophagy-inducing lead compound as a molecular probe, which was previously discovered in this laboratory, on colon cancer development and progression. Our proposed studies may not only provide insight into the pathogenesis of colon cancer, but also provide clues and strategies for the development of anti-colon cancer agents.