TMEM16A钙激活氯通道和ROCK1激酶相互激活促进ER阳性乳腺癌转移的机制研究

肿瘤转移是ER阳性乳腺癌主要死因，发现新靶点有望成为治疗乳腺癌转移的突破口。课题组发现雌二醇促进TMEM16A钙激活氯通道表达，TMEM16A高表达促进ER阳性乳腺癌细胞迁徙、侵袭、及抑制高剪切力诱导细胞死亡，表明TMEM16A参与迁移、侵袭、在循环系统存活等乳腺癌转移过程。TMEM16A通过EGFR/STAT3促进ROCK1蛋白表达，通过Src激活ROCK1；而ROCK1促进TMEM16A通道活性。本项目拟在明确ER通过靶向结合基因启动子促进TMEM16A表达的基础上，研究高表达TMEM16A通过EGFR/STAT3促进ROCK1表达；验证TMEM16A通过Src/RhoA激活ROCK1,而ROCK1通过磷酸化S466促进TMEM16A通道活性；进而揭示TMEM16A和ROCK1相互激活促进ER阳性乳腺癌转移的机制。研究成果为研发靶向TMEM16A治疗乳腺癌转移的药物提供理论和实验基础。

Metastasis is the leading cause of death in ER-positive breast cancer. Identification of new biomarkers will be a promising therapeutic strategy for treating metastasis of ER-positive breast cancer. We found that estradiol increased the expression of the Ca2+-activated chloride channel TMEM16A. TMEM16A overexpression promoted migration and invasion, and inhibited high shear stress-induced cell death in ER-positive breast cancer cells, suggesting that TMEM16A is involved in multiple metastatic processes such as migration, invasion and survival in the circulation system. In addition, we found that TMEM16A promoted the expression of ROCK1 proteins by activating the EGFR/STAT3 signaling pathway, and also activated ROCK1 via Src. In turn, ROCK1 increased TMEM16A channel activities. The purpose of this project is to identify the cellular mechanisms by which ER promotes TMEM16A expression by directly binding to the promoter region of the TMEM16A gene, to investigate the mechanisms by which TMEM16A increased ROCK1 expression via the EGFR/STAT3 signaling pathway, to explore the mutual activation mechanisms between TMEM16A and ROCK1, in which TMEM16A activates ROCK1 via Src and ROCK1 promotes TMEM16A channel activities by phosphorylating S466 in TMEM16A, and eventually to elucidate the mechanisms by which mutual activation between TMEM16A and ROCK1 promotes metastasis of ER-positive breast cancer. We believe that achieving these goals will provide the theoretical and experimental basis for the development of TMEM16A-targeted drugs for the treatment of metastasis in ER-positive breast cancer.