TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression.
TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression.
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DOI：
10.1158/1078-0432.ccr-17-1561
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发表时间：
2017-12-01
期刊：
影响因子：
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通讯作者：
Duvvuri U
中科院分区：
文献类型：
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作者：
Godse NR;Khan N;Yochum ZA;Gomez-Casal R;Kemp C;Shiwarski DJ;Seethala RS;Kulich S;Seshadri M;Burns TF;Duvvuri U
TMEM 16 A是一种钙激活的氯离子通道，在多种癌症中扩增，包括30%的头颈部鳞状细胞癌（HNSCC），提高了在恶性细胞中抗凋亡作用的可能性。本研究采用多模态的翻译研究。结合1）评估细胞活力、凋亡活化和蛋白表达的体外HNSCC细胞培养实验，2）评估类似结果的体内研究，和3）人HNSCC样品的分子和染色分析。发现TMEM 16 A表达与人HNSCC中更大的肿瘤尺寸、增加的Erk 1/2活性、更少的Bim表达和更少的总体凋亡活性相关。这些发现在随后的体外和体内研究中得到证实，并扩展到包括TMEM 16 A过表达的顺铂耐药表型。41例喉癌患者的队列研究表明，放化疗失败后复发的病例与TMEM 16 A过表达率高于未复发的HNSCC相关。最终，这项研究暗示TMEM 16 A通过限制细胞凋亡而成为肿瘤进展的贡献者，并作为更具侵袭性疾病的潜在生物标志物。
TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCC), raising the possibility of an anti-apoptotic role in malignant cells. The present study investigated this using a multi-modal, translational investigation. Combination of 1) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression 2) in vivo studies assessing similar outcomes, and 3) molecular and staining analysis of human HNSCC samples. TMEM16A expression was found to correlate with greater tumor size, increased Erk 1/2 activity, less Bim expression, and less apoptotic activity overall in human HNSCC. These findings were corroborated in subsequent in vitro and in vivo studies and expanded to include a cisplatin-resistant phenotype with TMEM16A overexpression. A cohort of 41 patients with laryngeal cancer demonstrated that cases that recurred after chemoradiation failure were associated with a greater TMEM16A overexpression rate than HNSCC that did not recur. Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease.