泛素连接酶复合物骨架蛋白CUL4B在调控肿瘤干细胞形成和自我更新中的作用及其机制研究

项目名称： 泛素连接酶复合物骨架蛋白CUL4B在调控肿瘤干细胞形成和自我更新中的作用及其机制研究

项目编号： No.81330050

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 龚瑶琴

作者单位： 山东大学

项目金额： 290万元

中文摘要： CUL4B是泛素连接酶复合物的骨架蛋白，我们前期发现CUL4B功能丧失导致人类发育异常和小鼠胚胎致死。最近我们发现CUL4B在乳腺癌、前列腺癌等多种肿瘤组织高表达；CUL4B复合物通过单泛素化H2AK119、协同PRC2调控包括p16、PTEN在内的多种抑癌基因；CUL4B通过抑制miRNA372-373而调控细胞周期蛋白CDK2表达进而影响DNA复制。由于肿瘤干细胞（CSCs)不仅是肿瘤发生的重要生物学基础，也是肿瘤转移、抵抗治疗和复发的重要机制，那么CUL4B促进肿瘤发生发展是不是通过调控CSCs实现的呢？为此，本课题将以乳腺癌、前列腺癌和结直肠癌为研究对象，研究CUL4B在CSCs形成和自我更新中的作用，发现CUL4B调控CSCs的关键分子及其调控机制，并分析CUL4B及其靶分子表达与肿瘤演进、转移和治疗抵抗等表型的相关性，为理解CUL4B在肿瘤发生发展中的作用机制提供理论依据。

中文关键词： C21_；乳腺肿瘤;肿瘤干细胞;自我更新;CUL4B;表观调控

英文摘要： CUL4B is a scaffold protein in ubiquitin E3 ligase complex. Our previous studies found developmental abnormality in patients with loss of function mutation in CUL4B, and embryonic lethality in Cul4b knock-out mice. Moreover, overexpression of CUL4B has been detected in many solid tumors such as breast cancer and prostate cancer. Further research has revealed that CUL4B complex, CRL4B, can catalyze H2AK119 monoubiquitination and coordinate with PRC2 to promote tumorigenesis via regulating many tumor suppressors including p16 and PTEN. Cancer stem cells are not only associated with tumor initiation and growth , but also play a crucial role in metastasis, drug resistance and relapse. Does CUL4B promote tumorigenesis through regulation of cancer stem cells? To test this hypothesis, we will study the regulation of expansion of cancer stem cells by CUL4B in breast cancer, prostate cancer, and colorectal cancer. We will also investigate the molecular mechanism, and identify the target genes of CUL4B in cancer stem cells. This can help understand biological functions of CUL4B in diseases and provide new targets for cancer treatment.

英文关键词： breast cancer ;cancer stem cells;self-renewal ;CUL4B ;epigenetic regulation