孕酮上调TMEM16A钙激活氯通道促进乳腺癌发生发展的机制研究

Identification of new prognostic and predictive markers can provide the possibility for individual treatment optimization for breast cancer patients.TMEM16A is overexpressed in breast cancer, and has been found to promote breast cancer tumorigenesis and progression. We have found that TMEM16A expression is higher in PR-positive breast cancer samples, and TMEM16A overexpression was associated with good prognosis in PR-positive breast cancer patients following tamoxifen treatment. These findings suggest that TMEM16A may be a potential new prognostic and predictive biomarker for breast cancer. However, the mechanisms by which TMEM16A is upregulated in breast cancer and TMEM16A overexpression promotes tumorigenesis and progression remain unclear. The purpose of this project is to investigate the mechanisms by which progesterone upregulates TMEM16A in breast cancer cells via progesterone receptor, to explore the mechanisms by which TMEM16A overexpression activates the CAMKII/RhoA/ROCK/moesin signaling pathway, and the CAMKII/RhoA/ROCK/moesin signaling pathway promotes TMEM16A chloride currents via moesin phosphorylation, and to identify the mechanisms by which TMEM16A promotes tumorigenesis and progression of breast cancer via the CAMKII/RhoA/ROCK/moesin signaling pathway. We believe that achieving these goals will shed a new light on the role of TMEM16A in PR-positive breast cancer, and targeting TMEM16A may be a novel therapeutic strategy for the treatment of PR-positive breast cancer with TMEM16A overexpression.

发现新的乳腺癌标记物是个体化药物治疗乳腺癌的最佳方案。TMEM16A钙激活氯通道在乳腺癌高表达，高表达TMEM16A与乳腺癌患者不良预后相关。课题组发现TMEM16A高表达与接受Tamoxifen治疗的PR阳性乳腺癌患者生存期延长显著相关。因此，TMEM16A可能成为新的乳腺癌预后和治疗预测标记物。然而，TMEM16A高表达的机制及其促进乳腺癌发生发展的机制尚不清楚。本项目拟研究孕酮通过其核受体促进TMEM16A在乳腺癌细胞上表达；TMEM16A高表达激活乳腺癌细胞CAMKII/RhoA/ROCK/moesin通路； CAMKII/RhoA/ROCK通路促进moesin磷酸化提高TMEM16A氯电流； TMEM16A通过CAMKII/RhoA/ROCK/moesin通路促进乳腺癌发生发展的机制。本课题为开发靶向TMEM16A的药物用于治疗高表达TMEM16A的PR阳性乳腺癌有重要指导作用。

TMEM16A钙激活氯通道在乳腺癌中高表达,TMEM16A高表达促进乳腺癌发生发展。然而，TMEM16A高表达的机制及其促进PR阳性乳腺癌发生发展的机制尚不清楚。我们应用Western blot、免疫组织化学、膜片钳等方法，发现TMEM16A在PR阳性乳腺癌中过表达；孕酮通过PR与TMEM16A启动子区域相结合而促进乳腺癌细胞TMEM16A表达。进一步发现 TMEM16A过表达通过激活EGFR/STAT3信号通路促进乳腺癌细胞体外增殖以及在体荷瘤生长。还发现TMEM16A过表达通过EGFR/STAT3上调PR-B表达并介导孕酮诱导的细胞增殖。TMEM16A抑制剂T16Ainh-A01以及转染具有低通道活性的TMEM16A突变体阻断孕酮诱导的EGFR/STAT3信号通路激活，PR-B表达上调以及细胞增殖，提示TMEM16A通道活性发挥促进EGFR/STAT3通路激活，PR-B表达上调以及细胞增殖的作用。另外，我们还发现TMEM16A促进乳腺癌ROCK1表达，并且ROCK1及磷酸化moesin-T558D促进TMEM16A钙激活氯通道活性。Moesin过表达促进TMEM16A通道活性，进而通过EGFR/STAT3信号通路介导TMEM16A促进乳腺癌细胞增殖的作用。因此，我们发现TMEM16A和PR之间的相互激活促进孕酮诱导的PR阳性乳腺癌增生的新机制；ROCK1/moesin促进TMEM16A通道活性进而促进乳腺癌发生发展。本研究为深入了解TMEM16A促进PR阳性乳腺癌发生发展提供新思路，为研究靶向TMEM16A治疗乳腺癌提供新方向。本项目研究成果发表相关论文10篇，其中 5 篇论文发表在SCI杂志 ，总影响因子达25.763。本项目共培养博士后6名、博士研究生 4名、硕士研究生 17 名。