TMEM16A inhibits autophagy and promotes the invasion of hypopharyngeal squamous cell carcinoma through mTOR pathway

• Published in: Carcinogenesis (New York) 2024-08, Vol.45 (8), p.569-581
• Main Authors: Yang, Xin, Cui, Limei, Liu, Zhonglu, Li, Yumei, Wu, Xinxin, Tian, Ruxian, Jia, Chuanliang, Ren, Chao, Mou, Yakui, Song, Xicheng
• Format: Article
• Language: English
• Subjects: Animals; Anoctamin-1 - genetics; Anoctamin-1 - metabolism; Apoptosis; Autophagy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Hypopharyngeal Neoplasms - genetics; Hypopharyngeal Neoplasms - metabolism; Hypopharyngeal Neoplasms - pathology; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Signal Transduction; Squamous Cell Carcinoma of Head and Neck - genetics; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; TOR Serine-Threonine Kinases - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgae020

Abstract Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared with normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy. High expression of TMEM16A in HNSCC and metastatic lymph nodes; TMEM16A can affect the invasion and proliferation of HNSCC in vivo and in vitro ; TMEM16A inhibits autophagy through mTOR pathway. Graphical Abstract Graphical Abstract