JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis.

Kun Ding, Xuqian Jiang, Jie Ni, Chao Zhang, Aiping Li, Jianwei Zhou

Ecotoxicology and environmental safety 2023 Jul 01

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Cigarette smoking is an independent risk factor for lung cancer. Nicotine, as an addictive substance in tobacco and e-cigarettes, is known to promote tumor progression and metastasis despite being a non-carcinogen. As a tumor suppressor gene, JWA is widely involved in the inhibition of tumor growth and metastasis and the maintenance of cellular homeostasis, including in non-small cell lung cancer (NSCLC). However, the role of JWA in nicotine-induced tumor progression remains unclear. Here, we reported for the first time that JWA was significantly downregulated in smoking-related lung cancer and associated with overall survival. Nicotine exposure reduced JWA expression in a dose-dependent manner. Gene Set Enrichment Analysis (GSEA) analysis showed the tumor stemness pathway was enriched in smoking-related lung cancer, and JWA was negatively associated with stemness molecules CD44, SOX2, and CD133. JWA also inhibited nicotine-enhanced colony formation, spheroid formation, and EDU incorporation in lung cancer cells. Mechanically, nicotine downregulated JWA expression via the CHRNA5-mediated AKT pathway. Lower JWA expression enhanced CD44 expression through inhibition of ubiquitination-mediated degradation of Specificity Protein 1 (SP1). The in vivo data indicated that JAC4 through the JWA/SP1/CD44 axis inhibited nicotine-triggered lung cancer progression and stemness. In conclusion, JWA via down-regulating CD44 inhibited nicotine-triggered lung cancer cell stemness and progression. Our study may provide new insights to develop JAC4 for the therapy of nicotine-related cancers. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Kun Ding, Xuqian Jiang, Jie Ni, Chao Zhang, Aiping Li, Jianwei Zhou. JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis. Ecotoxicology and environmental safety. 2023 Jul 01;259:115043