Skp2泛素化RIPK1参与结直肠癌细胞5-Fu耐药的分子机制

项目名称： Skp2泛素化RIPK1参与结直肠癌细胞5-Fu耐药的分子机制

项目编号： No.81502121

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 于新芳

作者单位： 中南大学

项目金额： 18万元

中文摘要： 结直肠癌是我国第五大致死性恶性肿瘤，5-Fu化疗耐药是导致结直肠癌治疗失败的重要原因。本项目前期研究发现在5-Fu敏感和耐药结直肠癌细胞内，5-Fu诱导的程序性坏死发生了明显改变。本项目将以泛素E3酶Skp2调控RIPK1的泛素化为切入点，从RIPK1的蛋白表达及功能活化两个方面研究Skp2对结直肠癌细胞5-Fu耐药的调控。确定Skp2通过影响RIPK1的生物学功能，从而抑制程序性坏死，导致结肠癌细胞5-Fu耐药的分子机制。并利用裸鼠移植瘤模型，在体内证实Skp2-RIPK1介导的程序性坏死抑制对结直肠癌5-Fu耐药的重要性。本研究将从程序性坏死及5-Fu化疗抵抗的角度阐明Skp2的生物学功能，为克服结直肠癌5-Fu耐药的临床治疗提供理论基础和实验证据。

中文关键词： 结；直肠肿瘤；RIPK1；Skp2；泛素化；程序性坏死

英文摘要： Colorectal cancer is the fifth leading cause of cancers in mortality in China, and chemotherapy resistance of 5-Fu is one of the major reasons which caused colorectal cancer clinic treatment failure. Our previous studies revealed that 5-Fu induced necroptosis was significantly disparate between sensitive and resistant colorectal cancer cells. In this study, we will illustrate the molecular mechanism of E3 ligase skp2 mediated 5-Fu chemotherapy resistance, and explore the underlying mechanism which involved in Skp2 regulated RIPK1 expression and activation via ubiquitination pathways. More importantly, we conducted xenograft model to evaluate the in vivo effect of Skp2-RIPK1 mediated necroptosis inhibition in colorectal cancer 5-Fu chemotherapy resistance. Our study will provide new ideas for the chemotherapy of colorectal cancer. Besides, it will have an important clinical significance and application prospects for targeted therapy and sensitizing chemotherapy.

英文关键词： Colorectal cancer;RIPK1;Skp2;ubiquitination;necroptosis