α5 nicotinic acetylcholine receptor (α5-nAChR) is associated with the progression of smoking-related lung adenocarcinoma (LUAD), but the molecular mechanism is unclear. Programmed death ligand 1 (PD-L1) is encoded by the CD274 gene, which not only inhibits the immune system, but also plays a unique role in tumor growth and metastasis. Here, we gained important insights into the underlying mechanism between α5-nAChR and PD-L1 in LUAD progression. α5-nAChR was overexpressed in various histological subtypes, cancer stages and metastasis statuses of LUAD. The group that coexpressed α5-nAChR and PD-L1 had a worse prognosis than the other subgroups at different stages of LUAD lymph node metastasis. The expression of α5-nAChR and PD-L1 was associated with epithelial-mesenchymal transition (EMT) marker CDH2. In vitro, α5-nAChR mediated nicotine-induced PD-L1 expression via STAT3 and the expression of EMT markers. Downregulation of α5-nAChR and/or PD-L1 inhibited EMT marker expression, cell proliferation, migration and invasion compared to silencing α5-nAChR or PD-L1 alone in LUAD cells. Furthermore, α5-nAChR expression was associated with PD-L1 and EMT marker expression in mouse xenograft models. These results highlight that α5-nAChR mediates STAT3/PD-L1 signaling, which contributes to cell migration and invasion. Therefore, our study may reveal a new interaction between α5-nAChR and PD-L1 that is involved in tumor cell growth and progression in LUAD, which may be a promising target for NSCLC diagnosis and immunotherapy.
Keywords: Epithelial–mesenchymal transition; Lung adenocarcinoma; PD-L1; STAT3; α5 nicotinic acetylcholine receptor.
© 2022. The Author(s) under exclusive licence to Japan Human Cell Society.