CCP6介导的谷氨酸化修饰调控膀胱癌干细胞自我更新及其肿瘤干预的分子机制研究

Bladder cancer is one of the most common malignancies, whose tumorigenesis has not been elucidated. Post-translational modifications of proteins have important roles in their functions and human tumorigenesis. Glutamylation modification have become the forefront and hotspot in biology research, and play important roles in biological process. However, little is known about the function and mechanism of glutamylation modification in cancer research. Our previous study found that expression of CCP6 was down-regulated in tumor tissues than in peri-tumor tissues. CCP6-/- mice tended to be induced to form bladder tumors compared with wide type mice. Furthermore, CCP6 depletion promotes the capacity of cancer stem cell proliferation and onco-sphere formation. We identified several candidate substrates with enzyme inactivated CCP6. This project will further investigate the functions of CCP6 mediated glutamylation modification in human bladder tumorigenesis. We will identify specific substrate of CCP6 and self-renewal signaling pathway mediated by glutamylation modification. Then, we will examine the relationship between glutamylation modification mediated by CCP6 and prognosis of bladder cancer patients. Taken together, this project will provide new insights into the function and molecular mechanism for glutamylation modification in bladder tumorigenesis and help to reveal more effective treatment targets for bladder cancer.

膀胱癌为泌尿系最常见的恶性肿瘤，其发病机制尚未明了。近年来发现，蛋白质谷氨酸化修饰参与多种生命过程的调节，谷氨酸化修饰与疾病的关系也成为当今研究的热点，而在泌尿系肿瘤中的功能还未见报道。我们初步研究发现，羧肽酶CCP6在膀胱癌干细胞中低表达，CCP6基因敲除小鼠极易诱发膀胱癌癌，表明CCP6介导的谷氨酸化修饰参与膀胱癌的发生发展过程。CCP6沉默的肿瘤细胞增殖和成球能力显著增强。我们表达了酶活性失活的CCP6，鉴定了CCP6的数个候选底物。在此基础上，本课题将深入研究CCP6介导的谷氨酸化修饰在膀胱癌干细胞自我更新中的作用，明确谷氨酸化修饰与膀胱癌发生的关系。鉴定出CCP6致癌的作用底物以及谷氨酸化修饰介导的信号通路，分析CCP6介导的谷氨酸化修饰参与膀胱癌化疗药物耐药的调控作用，以期揭示谷氨酸化修饰调节膀胱癌干细胞自我更新的分子机制，为膀胱癌的诊断和治疗提供新靶点。

膀胱癌为泌尿系最常见的恶性肿瘤，其发病机制尚未明了。近年来发现，蛋白质谷氨酸化修饰参与多种生命过程的调节，谷氨酸化修饰与疾病的关系也成为当今研究的热点，而在泌尿系肿瘤中的功能还未见报道。我们初步研究发现，羧肽酶CCP6在膀胱癌组织及膀胱癌干细胞中低表达，CCP6基因敲除小鼠极易诱发膀胱癌，CCP6沉默的肿瘤干细胞增殖和成球能力显著增强，表明CCP6介导的谷氨酸化修饰参与膀胱癌的发生发展过程。我们表达了酶活性失活的CCP6，鉴定了CCP6的数个候选底物。在此基础上，本课题将深入研究CCP6介导的谷氨酸化修饰在膀胱癌发病中的作用，明确谷氨酸化修饰与膀胱癌干性维持的关系。鉴定出CCP6致癌底物以及谷氨酸化修饰介导的干细胞相关信号通路，以期揭示谷氨酸化修饰调节膀胱癌发病的分子机制，并设计相应的激动剂和抑制剂，在体观察荷瘤动物的抑瘤作用，为膀胱癌的诊断和治疗提供新靶点。