α5-nAChR associated with Ly6E modulates cell migration via TGF-β1/Smad signaling in non-small cell lung cancer
Qian Zhang, Ying Jia, Pan Pan, Xiuping Zhang, Yanfei Jia, Ping Zhu, Xiaowei Chen, Yang Jiao, Guiyu Kang, Lulu Zhang, Xiaoli Ma
Abstract
The α5-nicotinic acetylcholine receptor (α5-nAChR) is closely associated with nicotine-related lung cancer, offering a novel perspective for investigating the molecular pathogenesis of this disease. However, the mechanism by which α5-nAChR functions in lung carcinogenesis remains to be elucidated. Lymphocyte antigen 6 (Ly6) proteins, like snake three-finger alpha toxins such as α-bungarotoxin, can modulate nAChR signaling. Ly6E, a member of the Ly6 family, is a biomarker of poor prognosis in smoking-induced lung carcinogenesis and is involved in the regulation of TGF-β1/Smad signaling. Here, we explored the underlying mechanisms linking α5-nAChR and Ly6E in non-small cell lung cancer (NSCLC). The expression of α5-nAChR was correlated with Ly6 expression, smoking status and lower survival in NSCLC tissues. In vitro, α5-nAChR mediated Ly6E, the phosphorylation of the TGF-β1 downstream molecule Smad3 (pSmad3, a key mediator of TGF-β1 signaling), the epithelial-mesenchymal transition (EMT) markers Zeb1, N-cadherin and vimentin expression in NSCLC cells. The downregulation of Ly6E reduced α5-nAChR, pSmad3, Zeb1, N-cadherin and vimentin expression. Functionally, silencing both α5-nAChR and Ly6E significantly inhibited cell migration compared to silencing α5-nAChR or Ly6E alone. Furthermore, the functional effects of α5-nAchR and Ly6E were confirmed in chicken embryo chorioallantoic membrane (CAM) and mouse xenograft models. Therefore, our findings uncover a new interaction between α5-nAChR and Ly6E that inhibits cancer cell migration by modulating the TGF-β1/Smad signaling pathway in NSCLC, which may serve as a novel target for therapeutic intervention.