A mutual activation loop between the Ca2+-activated chloride channel TMEM16A and EGFR/STAT3 signaling promotes breast cancer tumorigenesis
A mutual activation loop between the Ca2+-activated chloride channel TMEM16A and EGFR/STAT3 signaling promotes breast cancer tumorigenesis
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Ca2 激活氯离子通道 TMEM16A 和 EGFR/STAT3 信号之间的相互激活环促进乳腺癌肿瘤发生
DOI：
10.1016/j.canlet.2019.04.027
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Xiao, Qinghuan
中科院分区：
文献类型：
--
作者：
Wang, Hui;Yao, Fan;Xiao, Qinghuan
钙激活的氯离子通道TMEM16A(Anoctamin 1)在乳腺癌中过度表达。目前尚不清楚TMEM16A过度表达如何在乳腺癌的发生中发挥作用。在这项研究中，我们发现，在未接受他莫昔芬治疗的ER阳性乳腺癌患者中，TMEM16A的高表达与EGFR或STAT3的高表达显著相关，而在接受他莫昔芬治疗的患者中，TMEM16A的高表达与总生存期的延长显著相关。EGF激活EGFR/STAT3信号通路可促进乳腺癌细胞TMEM16A的表达，而TMEM16A过表达则激活了EGFR/STAT3信号通路。体外和动物研究均表明，TMEM16A过表达促进乳腺癌细胞增殖和肿瘤生长。此外，TMEM16A过表达诱导的细胞增殖可被EGFR/STAT3抑制剂阻断，TMEM16A基因敲除可减少EGF诱导的乳腺癌增殖和肿瘤发生。此外，抑制TMEM16A通道功能有效地抑制了乳腺癌细胞的增殖，特别是与EGFR抑制剂联合使用时。我们的发现确定了TMEM16A和EGFR/STAT3信号之间的相互激活环，这对乳腺癌的增殖和生长是重要的。抑制TMEM16A可能代表了一种治疗EGFR表达的乳腺癌的新方法。
The Ca2+-activated chloride channel TMEM16A (anoctamin 1) is overexpressed in breast cancer. It remains unclear how TMEM16A overexpression plays a role in carcinogenesis in breast cancer. In this study, we found that high TMEM16A expression in combination with high EGFR or STAT3 expression was significantly associated with shorter overall survival in ER-positive breast cancer patients without tamoxifen treatment, and longer overall survival in patients with tamoxifen treatment. EGFR/STAT3 signaling activation by EGF promoted TMEM16A expression, and TMEM16A overexpression activated EGFR/STAT3 signaling in breast cancer cells. Both in vitro and in animal studies showed that TMEM16A overexpression promoted, and TMEM16A knockdown inhibited breast cancer cell proliferation and tumor growth. In addition, TMEM16A overexpression-induced cell proliferation was blocked by EGFR/STAT3 inhibitors, and TMEM16A knockdown reduced EGF-induced proliferation and tumorigenesis in breast cancer. Furthermore, inhibition of TMEM16A channel function effectively reduced breast cancer cell proliferation, especially in combination with EGFR inhibitors. Our findings identify a mutual activation loop between TMEM16A and EGFR/STAT3 signaling, which is important for breast cancer proliferation and growth. TMEM16A inhibition may represent a novel therapy for EGFR-expressing breast cancer.