SCAMP1通过上调Integrin αV介导细胞自噬促进结直肠癌奥沙利铂化疗耐药的机制研究

奥沙利铂化疗是结直肠癌患者最常用的治疗方法之一，而奥沙利铂耐药导致的疗效不佳是急需解决的临床难题。SCAMP1参与多个肿瘤的发展及耐药机制，但在结直肠癌中的作用尚待阐明。泛素化在抗肿瘤药物疗效调控中发挥重要作用。我们前期研究发现，结直肠癌奥沙利铂耐药细胞中SCAMP1泛素化水平降低，细胞自噬水平升高，且敲低SCAMP1显著抑制耐药细胞自噬水平。接着我们预测出可能与SCAMP1存在蛋白相互作用的自噬相关蛋白Integrin αV，并验证了SCAMP1和Integrin αV的蛋白相互作用，且联合敲低SCAMP1和Integrin αV进一步抑制耐药细胞自噬。基于本领域研究现状和以上基础，本项目拟从SCAMP1泛素化的角度切入，以SCAMP1-Integrin αV信号轴为研究主体，探索其在细胞自噬、奥沙利铂耐药中的具体机制，有利于推动结直肠癌化疗耐药的研究，为寻找增敏靶点提供线索和实验依据。

Oxaliplatin-based regimen is one of the most commonly used treatments for patients with colorectal cancer, however the poor survival rate caused by oxaliplatin resistance remains to be a huge clinical problem. SCAMP1 is involved in the development and drug resistance of multiple tumors, but its role in colorectal cancer remains unclear. Ubiquitination plays an important role in the regulation of the efficacy of the chemotherapeutic agents. Our previous study found that SCAMP1 ubiquitination levels were reduced and autophagy level increased in oxaliplatin-resistant colorectal cancer cell line, and knockdown of SCAMP1 significantly inhibited autophagy level in such cell line. Then the autophagy-related protein Integrin αV that might directly interact with SCAMP1 was predicted through database online, and the protein-protein interactions between SCAMP1 and Integrin αV was verified. Furthermore, the autophagy level of oxaliplatin-resistant colorectal cancer cell was found further inhibited by double knockdown of SCAMP1 and Integrin αV. Based on the research actuality in this field and our foundation above, and starting from the standpoint of SCAMP1 ubiquitination, we try to explore the regulatory mechanism of SCAMP1-Integrin αV signal axis against cell autophagy and oxaliplatin resistance in colorectal cancer. We believe this project may favor the development of research against colorectal cancer chemoresistance, and provides clues and experimental basis for oxaliplatin efficacy improvement.