肿瘤干细胞标志物CD133与DNA甲基化酶DNMT1相互作用的功能和机制

项目名称： 肿瘤干细胞标志物CD133与DNA甲基化酶DNMT1相互作用的功能和机制

项目编号： No.81472724

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 魏湲颜

作者单位： 复旦大学

项目金额： 72万元

中文摘要： 肿瘤干细胞标志物CD133在肿瘤启动、耐药、侵袭中发挥着重要的功能，有望成为肿瘤治疗的新靶点。然而CD133 直接介导的信号通路不明，成为其在肿瘤干细胞分选、功能研究和临床应用的瓶颈之一。我们前期研究发现:(1)CD133能定位于胶质瘤干细胞细胞核;(2)核定位CD133能与DNA甲基化酶DNMT1相互作用，继而抑制肿瘤干细胞自我更新维持基因p21的启动子甲基化;(3)CD133籍此激活p21转录，从而促进胶质瘤干细胞自我更新。鉴于此，本项目拟利用人胶质瘤标本、胶质瘤干细胞模型和小鼠胶质瘤原位模型，阐释CD133和DNMT1相互作用的机制、调控因素及其在胶质瘤干细胞自我更新、成瘤、耐药中的功能和机制，有望首次揭示出维持胶质瘤干细胞自我更新的核CD133-DNMT1-p21信号轴，发现不同于膜定位CD133的信号通路，为了解胶质瘤干细胞自我更新的分子机制、开展肿瘤干细胞的靶向治疗提供新思路。

中文关键词： C15_脑；中枢神经系统肿瘤；肿瘤干细胞；CD133；DNMT1；相互作用

英文摘要： CD133, a widely known marker of cancer stem cell, plays critical roles in tumor initiation, invasion, migration and drug-fast. Thus, CD133 has been considered as a new target for cancer therapy. However, CD133-mediaed signaling pathways remain largely known. Our previous study showed that CD133 was located in the nuclear of glioma stem cell. The nuclear localization of CD133 was correlated with histopathological grade and glioma recurrence. Furthermore, CD133 physically interacted with DNA methyltransferase 1 (DNMT1) and regulated the transcription and promoter methylation of DNMT1 target gene p21. CD133 regulates glioma stem cell self-renewal through up-regulation of p21 transcription. Increasing evidence show that p21 promotes genomic stability in cancer stem cells and maintains the self-renewal capacity of cancer stem cells. Thus, we speculate that the interaction between nuclear CD133 and DNMT1 might regulate the self-renewal of glioma stem cell through regulation p21 promoter methylation. In this project, we intend to uncover the molecular mechanism and biological function of the interaction between CD133 and DNMT1 in glioma stem cell self-renewal, quiescence, drug-fast and tumor initiation. Through these efforts, firstly, we hope to illuminate nuclear CD133-DNMT1-p21 signaling axis, thus exploring the mechanism and function of CD133 nuclear localization. Second, this project will uncover the mechanism maintain glioma stem cell self-renewal, thus providing clues to target glioma stem cell.

英文关键词： glioma;cancer stem cell;CD133;DNMT1;interaction