肌动蛋白调节因子KIAA1211通过调控YAP核转位抑制结直肠癌干性及转移的分子机制研究

结直肠癌复发转移是临床中的突出难题，结直肠癌干细胞研究为该治疗困境提供了新的思路。本项目组模拟肿瘤物理微环境构建结直肠癌肿瘤再生细胞（tumor repopulating cells，TRCs）模型，用于探索结直肠癌干性和转移调控机制。通过前期研究发现:结直肠癌TRCs中肌动蛋白解聚与结直肠癌干性和转移密切相关；结合RNA测序和生物信息学研究筛选出在TRCs中低表达的肌动蛋白调节因子KIAA1211,进一步研究发现KIAA1211表达受细胞外基质硬度调控，在结直肠癌TRCs中表达下调，促进YAP出核，干预TRCs干性及转移。基于以上结果，我们推测KIAA1211-F-actin-YAP信号轴是调控结直肠癌干性和转移的新机制。本项目拟从离体细胞实验、动物模型、临床标本三个层面探索并验证KIAA1211调控结直肠癌干性及转移的作用和机制，以期为结直肠癌基础及临床研究提供新的策略。

Recurrence and metastasis are prominent clinical problems of colorectal cancer treatment.Colorectal cancer stem cell theory provides a new idea for this dilemma. Coloretal tumor repopulating cells (TRCs) research model was constructed to explore the mechanism of colorectal cancer stemness and metastasis by simulating tumor mechanical microenvironment . Our preliminary study show that depolymerization of F-actin is closely associated with stemness and metastasis of colorectal cancer. KIAA1211 was identified as actin regulatory gene, which is altered by matrix stiffness and is downregulated in TRCs through RNA sequening and bioinformatics study. Decreased KIAA1211 expression induces YAP nucleocytoplasmic shuttling and then affects stemness and metastasis of TRCs. Thus, we suspect KIAA1211-F-actin-YAP signal axis may be the new machanism to regulate stemness and metastasis of colorectal cancer. By in vitro cell experiments, animal models, and clinical specimens testing，this project intends to explore and verify the role and mechanism of KIAA1211 in regulating the stemness and metastasis of colorectal cancer. The completion of this project will provide new strategies for basic and clinical research of colorectal cancer.