E3泛素连接酶RNF8在乳腺癌转移中的作用及机制研究

项目名称： E3泛素连接酶RNF8在乳腺癌转移中的作用及机制研究

项目编号： No.81672859

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 李莉

作者单位： 北京大学

项目金额： 25万元

中文摘要： 肿瘤转移是一个多步骤多因素参与的复杂过程，其间上皮细胞向间质细胞的变迁(epithelial-mesenchymal transition, EMT) 本质上是一个细胞重编程和转分化的过程，组蛋白修饰等表观遗传学变化发挥重要作用。揭示EMT过程中细胞重编程的调控因素，对于阐明肿瘤转移机制具有重要意义。RNF8是一个泛素E3连接酶，通过对组蛋白进行泛素化修饰而在DNA损伤修复、精子发育中起重要作用，但是其在肿瘤转移中的作用尚不清楚。我们前期研究发现RNF8促进乳腺癌细胞EMT的发生，本项目拟在此基础上研究RNF8在EMT和乳腺癌转移中的作用；分离、鉴定RNF8与肿瘤转移相关的作用因子；阐明RNF8介导EMT和乳腺癌转移的分子机制。此项研究对于揭示RNF8的功能和乳腺癌转移具有重要意义，并将为针对RNF8的抗癌药物的研发提供新靶标。

中文关键词： C21_乳腺肿瘤；；E3泛素连接酶RNF8；上皮-间质变迁；肿瘤转移

英文摘要： The epithelial to mesenchymal transition (EMT) contributes to tumor progression and has a critical role in the formation and development of metastasis. EMT is triggered by a diverse set of stimuli that can lead to stable reprogramming of epithelial cells to mesenchymal states; however, the underlying mechanism is remains elusive. RNF8 is an ubiquitin E3 ligase with C-terminal RING domain that can catalyze the formation of both K63- and K48-linked ubiquitin chains when coupled with distinct conjugating E2s. RNF8 plays essential roles in DNA damage response and spermatogenesis through mediating histone ubiquitination. Therefore, it is assumed that RNF8 might be also involved in the development and progression of tumor. However, whether and how RNF8 might be implicated in tumorigenesis is currently unkown. Recently, we found that ectopic expression of RNF8 in MCF-7 breast cancer cells could reduce the expression of E-Cadherin, a marker of epithelial, and inhibit cell migration; while depletion of RNF8 in MDA-MB-231 breast cancer cells led to the decrease of a mesenchymal marker, Vimentin, as well as the increase of E-Cadherin and promoted cell migration. More importantly, the expression of RNF8 is positively correlated with lymph node metastases in human breast cancer tissues. These results suggest that RNF8 is associated with EMT and breast cancer metastasis. This study is aimed to investigate the role of RNF8 in EMT and breast cancer metastasis, and to elucidate the underlying mechanism mediated by RNF8-dependent ubiquitination. This research will provide novel insight into the function of RNF8 and the molecular mechanism underlying RNF8-mediated metastasis. It will also have important implications in the development of novel potential targets for intervention of breast cancer metastasis.

英文关键词： breast cancer;E3 ubiquitin ligase RNF8;epithelial-mesenchymal transition; EMT;tumor metastasis