TMEM16A/ANO1 Inhibits Apoptosis Via Downregulation of Bim Expression.

Abstract

<b>Purpose:</b> TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation.<b>Experimental Design:</b> Combination of (i) <i>in vitro</i> HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) <i>in vivo</i> studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples.<b>Results:</b> 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 <i>in vitro</i> and <i>in vivo</i> 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.<b>Conclusions:</b> Ultimately, this study implicates TMEM16A as a contributor to tumor progression by limiting apoptosis and as a potential biomarker of more aggressive disease. <i>Clin Cancer Res; 23(23); 7324-32. ©2017 AACR</i>.