The α9 Nicotinic Acetylcholine Receptor Mediates Nicotine-Induced PD-L1 Expression and Regulates Melanoma Cell Proliferation and Migration

Cigarette smoking is associated with an increased risk of melanoma metastasis. Smokers show higher PD-L1 expression and better responses to PD-1/PD-L1 inhibitors than nonsmokers. Here, we investigate whether nicotine, a primary constituent of tobacco, induces PD-L1 expression and promotes melanoma c...

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Bibliographic Details
Published in:Cancers 2019-12, Vol.11 (12), p.1991
Main Authors: Nguyen, Hai Duong, Liao, You-Cheng, Ho, Yuan-Soon, Chen, Li-Ching, Chang, Hui-Wen, Cheng, Tzu-Chun, Liu, Donald, Lee, Woan-Ruoh, Shen, Shing-Chuan, Wu, Chih-Hsiung, Tu, Shih-Hsin
Format: Article
Language:English
Subjects:
Acetylcholine receptors (nicotinic)
AKT protein
Breast cancer
Cell activation
Cell growth
Cell lines
Cell migration
Cell proliferation
Cigarette smoking
Gene expression
Genotype & phenotype
Immune system
Immunotherapy
Ligands
Lung cancer
Lymph nodes
Medical prognosis
Melanoma
Mesenchyme
Metastases
Metastasis
Nicotine
PD-1 protein
PD-L1 protein
Proteins
Signal transduction
Skin cancer
Smoking
Stat3 protein
Tobacco smoke
Tumors
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Summary:Cigarette smoking is associated with an increased risk of melanoma metastasis. Smokers show higher PD-L1 expression and better responses to PD-1/PD-L1 inhibitors than nonsmokers. Here, we investigate whether nicotine, a primary constituent of tobacco, induces PD-L1 expression and promotes melanoma cell proliferation and migration, which is mediated by the α9 nicotinic acetylcholine receptor (α9-nAChR). α9-nAChR overexpression in melanoma using melanoma cell lines, human melanoma tissues, and assessment of publicly available databases. α9-nAChR expression was significantly correlated with PD-L1 expression, clinical stage, lymph node status, and overall survival (OS). Overexpressing or knocking down α9-nAChR in melanoma cells up- or downregulated PD-L1 expression, respectively, and affected melanoma cell proliferation and migration. Nicotine-induced α9-nAChR activity promoted melanoma cell proliferation through stimulation of the α9-nAChR-mediated AKT and ERK signaling pathways. In addition, nicotine-induced α9-nAchR activity promoted melanoma cell migration via activation of epithelial-mesenchymal transition (EMT). Moreover, PD-L1 expression was upregulated in melanoma cells after nicotine treatment via the transcription factor STAT3 binding to the PD-L1 promoter. These results highlight that nicotine-induced α9-nAChR activity promotes melanoma cell proliferation, migration, and PD-L1 upregulation. This study may reveal important insights into the mechanisms underlying nicotine-induced melanoma growth and metastasis through α9-nAChR-mediated carcinogenic signals and PD-L1 expression.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers11121991