Department of Medical Laboratory, Weifang Medical University, Weifang, 261053, China.
Jinan Central Hospital, Shandong University, Jinan, 250013, China.
Hum Cell. 2022 Jul;35(4):1207-1218. doi: 10.1007/s13577-022-00709-1. Epub 2022 May 20.
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.
α5 型烟碱型乙酰胆碱受体 (α5-nAChR) 与吸烟相关的肺腺癌 (LUAD) 的进展有关，但分子机制尚不清楚。程序性死亡配体 1 (PD-L1) 由 CD274 基因编码，它不仅抑制免疫系统，而且在肿瘤生长和转移中发挥独特作用。在这里，我们深入了解了 LUAD 进展中 α5-nAChR 与 PD-L1 之间的潜在机制。α5-nAChR 在 LUAD 的各种组织学亚型、癌症分期和转移状态中过度表达。在 LUAD 淋巴结转移的不同阶段，共表达 α5-nAChR 和 PD-L1 的组比其他亚组的预后更差。α5-nAChR 和 PD-L1 的表达与上皮-间充质转化 (EMT) 标志物 CDH2 有关。在体外，α5-nAChR 通过 STAT3 和 EMT 标志物的表达介导尼古丁诱导的 PD-L1 表达。与单独沉默 α5-nAChR 或 PD-L1 相比，下调 α5-nAChR 和/或 PD-L1 可抑制 LUAD 细胞中 EMT 标志物的表达、细胞增殖、迁移和侵袭。此外，α5-nAChR 的表达与小鼠异种移植模型中的 PD-L1 和 EMT 标志物表达相关。这些结果强调了 α5-nAChR 介导 STAT3/PD-L1 信号通路，这有助于细胞迁移和侵袭。因此，我们的研究可能揭示了 α5-nAChR 与 PD-L1 之间涉及 LUAD 肿瘤细胞生长和进展的新相互作用，这可能是 NSCLC 诊断和免疫治疗的有前途的靶点。
