肠上皮自噬调控免疫逃逸促进炎性肠癌发生发展的机制研究

Colitis-associated cancer(CAC) is closely related with inflammatory bowel disease(IBD),while the exact pathogenesis of CAC is not fully understood. Physiological changes of intestinal epithelium cells themselves are particularly important for the development of colotis and colorectal cancer. Our previous studies demonstrated that regulation of autophagy could impact colorectal tumor initiation and development, however, there are few studies on the direct regulation by intestinal epithelial autophagy. Intestinal epithelial cell-specfic knockout mice of Atg7 gene could restrain AOM/DSS induced colon tumor, and result in a significant decrease in tumor number and tumor load. Preliminary research on mechanisms found that deletion of Atg7 in intestinal epithelial cells aggravates the immune inflammatory response, which suggest that intestinal epithelial autophagy may regulate immune escape to promote CAC. In this project, We will further clarify that intestinal epithelial autophagy can regulate the initiation and development of CAC and participate in tumor escape, and explore the molecular mechanism of intestinal epithelial autophagy regulating immune escape in promoting CAC in the clinical, animal, and molecular levels. Our research will provide new insights on theoretical basis on the early prognosis, prevention and immunotherapy of CAC.

炎症相关性肠癌（CAC）与炎症性肠病密切相关，但其致病机制尚不明确。肠上皮作为参与肠炎及肠癌发生发展的重要组分，其自身的各种生理变化对肠炎及肠癌的发生发展尤为重要。我们前期发现自噬调节剂可以调控CAC发生发展，但肠上皮自噬能够直接调控这一过程的研究较少。我们用AOM/DSS诱导肠上皮Atg7基因敲除小鼠发生CAC，发现肿瘤数目、肿瘤负荷明显减少。初步机制研究发现肠上皮Atg7基因缺失增强了抗肿瘤免疫反应，提示肠上皮自噬可能通过调控免疫逃逸促进CAC发生发展。本课题拟结合临床标本、动物模型、分子实验进一步明确肠上皮自噬能够调控CAC的发生发展并参与肿瘤的免疫逃逸过程，深入探索肠上皮自噬调控免疫逃逸促进CAC发生发展的分子机制。这些研究将为CAC的早期诊断、预防及相关的免疫治疗提供新的理论依据。

炎症相关性肠癌与炎症性肠病密切相关，但其致病机制尚不明确。自噬对肠上皮细胞功能及维持肠道稳态具有重要作用。我们利用AOM/DSS诱导炎性肠癌模型来探究自噬在CAC发生发展中的作用及机制。研究结果显示，肠上皮Atg7缺失导致肠道肿瘤数目、大小及负荷明显减少。机制研究发现自噬通过维持上皮屏障功能和激活STAT3/ERK信号通路促进上皮细胞的存活和增殖。此外，研究还发现肠上皮Atg7缺失增强了抗肿瘤免疫反应，包括CD8+T细胞增加，趋化因子CCL4、CCL5和关键细胞因子IFNγ表达上调。这些发现揭示了自噬在激活结肠保护、再生和肿瘤发生过程中的重要作用，将为CAC的预防及治疗提供一定的理论依据。