Low-Dose Nicotine Activates EGFR Signaling via ?5-nAChR and Promotes Lung Adenocarcinoma Progression.

ABSTRACT: Nicotine in tobacco smoke is considered carcinogenic in several malignancies including lung cancer. The high incidence of lung adenocarcinoma (LAC) in non-smokers, however, remains unexplained. Although LAC has long been less associated with smoking behavior based on previous epidemiological correlation studies, the effect of environmental smoke contributing to low-dose nicotine exposure in non-smoking population could be underestimated. Here we provide experimental evidence of how low-dose nicotine promotes LAC growth in vitro and in vivo. Screening of nicotinic acetylcholine receptor subunits in lung cancer cell lines demonstrated a particularly high expression level of nicotinic acetylcholine receptor subunit ?5 (? 5-nAChR) in LAC cell lines. Clinical specimen analysis revealed up-regulation of ? 5-nAChR in LAC tumor tissues compared to non-tumor counterparts. In LAC cell lines ? 5-nAChR interacts with epidermal growth factor receptor (EGFR), positively regulates EGFR pathway, enhances the expression of epithelial-mesenchymal transition markers, and is essential for low-dose nicotine-induced EGFR phosphorylation. Functionally, low-dose nicotine requires ? 5-nAChR to enhance cell migration, invasion, and proliferation. Knockdown of ? 5-nAChR inhibits the xenograft tumor growth of LAC. Clinical analysis indicated that high level of tumor ? 5-nAChR is correlated with poor survival rates of LAC patients, particularly in those expressing wild-type EGFR. Our data identified ? 5-nAChR as an essential mediator for low-dose nicotine-dependent LAC progression possibly through signaling crosstalk with EGFR, supporting the involvement of environmental smoke in tumor progression in LAC patients.

SUBMITTER: Wang ML 

PROVIDER: S-EPMC7555382 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature