@article{543d21a107b6499cb84e61ca9c7bfd92,
title = "Low-dose nicotine activates egfr signaling via α5-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 α5 (α 5-nAChR) in LAC cell lines. Clinical specimen analysis revealed up-regulation of α 5-nAChR in LAC tumor tissues compared to non-tumor counterparts. In LAC cell lines α 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 α 5-nAChR to enhance cell migration, invasion, and proliferation. Knockdown of α 5-nAChR inhibits the xenograft tumor growth of LAC. Clinical analysis indicated that high level of tumor α 5-nAChR is correlated with poor survival rates of LAC patients, particularly in those expressing wild-type EGFR. Our data identified α 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.",
keywords = "EGFR, Environmental smoke, Lung adenocarcinoma, Nicotine, α 5-nAChR",
author = "Wang, {Mong Lien} and Hsu, {Yi Fan} and Liu, {Chih Hsuan} and Kuo, {Ya Ling} and Chen, {Yi Chen} and Yeh, {Yi Chen} and Ho, {Hsiang Ling} and Wu, {Yu Chung} and Chou, {Teh Ying} and Wu, {Cheng Wen}",
note = "Funding Information: The α5-nAChR overexpression plasmid was purchased from Thermo (MHS1010-7508410), which contains full length α5-nAChR cDNA. The shRNA against α5-nAChR (ID: TRCN0000061135; target sequence: CCTTCAGAACTGTTCCATGAA) and EGFR (ID: TRCN0000121068; target sequence: GCCACAAAGCAGTGAATTTAT) were obtained from the National RNAi Core Facility at the Genomic Research Center, Academia Sinica, supported by the National Core Facility Program for Biotechnology Grants of NSC (NSC 104-2319-B-001-002). Funding Information: Funding: This study was funded in part by the Ministry of Science and Technology (MOST-106-2320-B-075-002, MOST-107-2633-B-009-003, 108-2320-B-009-002, and 109-2320-B-075-001), Taipei Veterans General Hospital (V107B-017, V108D46-004-MY2-2, and V108E-006-4), and Yen-Tjing-Ling Medical Foundation (CI-108-11), Taiwan. Funding Information: Acknowledgments: We thank Yuan-Soon Ho and Chia-Hwa Lee for discussion and support in the initiation of this study and Mei-Yu Chen for critical review and comments on the manuscript. We acknowledge the technical support from the Taiwan Mouse Clinic funded by the National Research Program for Biopharmaceuticals (NRPB) of Taiwan. We thank Ming-Long Tsai for technical support in animal experiments. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = sep,
doi = "10.3390/ijms21186829",
language = "English",
volume = "21",
pages = "1--18",
journal = "International journal of molecular sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "18",
}