Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, 110122, China.
Department of Anesthesiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Mol Cancer. 2017 Sep 11;16(1):152. doi: 10.1186/s12943-017-0720-x.
TMEM16A (known as anoctamin 1) Ca-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.
TMEM16A（也称为anoctamin 1）是一种钙离子激活的氯离子通道，在许多肿瘤中过度表达。在许多 11q13 扩增的肿瘤中，TMEM16A 的过度表达可能是由于基因扩增引起的。在许多癌细胞中，TMEM16A 的表达还通过转录调控、表观遗传调控和 microRNAs 进行调控。此外，TMEM16A 在不同的癌症中激活不同的信号通路，例如乳腺癌中的 EGFR 和 CAMKII 信号通路、肝癌中的 p38 和 ERK1/2 信号通路、头颈部鳞状细胞癌和膀胱癌中的 Ras-Raf-MEK-ERK1/2 信号通路以及神经胶质瘤中的 NFκB 信号通路。此外，已有报道称 TMEM16A 过度表达在不同的癌细胞中促进、抑制或对细胞增殖和迁移没有影响。由于 TMEM16A 通过激活不同的信号通路在不同的癌细胞中发挥不同的作用，我们试图提出 TMEM16A 通过一种依赖于细胞的机制调节癌细胞增殖和迁移的观点。TMEM16A 的细胞特异性作用可能取决于特定癌症类型特有的 TMEM16A 过度表达机制所预先确定的细胞环境。TMEM16A 可能通过其相关的蛋白质网络、不同激酶的磷酸化以及不同信号通路的参与来发挥其细胞特异性作用。此外，我们还讨论了 TMEM16A 通道活性在癌症中的作用及其在不同癌症中作为预后和预测标志物的临床应用。本综述强调了 TMEM16A 在癌症中的细胞类型特异性机制，并设想了 TMEM16A 抑制剂作为 TMEM16A 过表达癌症潜在治疗方法的有前途的用途。
