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The α5-nAChR/PD-L1 axis facilitates lung adenocarcinoma cell migration and invasion

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Abstract

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.

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Funding

This work was supported by the [Natural Science Foundation of Shandong Province] [Grant (ZR2021MH322 and ZR2018MH021)]; [National Natural Science Foundation of China] (Grant No: 3197072).

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Authors and Affiliations

  1. Department of Medical Laboratory, Weifang Medical University, Weifang, 261053, China

    Ping Zhu, Guiyu Kang & Xiaoli Ma

  2. Jinan Central Hospital, Shandong University, Jinan, 250013, China

    Yang Jiao, Xiangying Li & Xiaoli Ma

  3. Research Center of Basic Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China

    Chengzhi Gui, Huiping Fan, Yanfei Jia, Lulu Zhang & Xiaoli Ma

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  1. Ping Zhu
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Contributions

PZ and XM wrote the first draft of the manuscript. PZ and XM contributed to the conception and design of the research. PZ, GK, YJ, CG, HF, XL, YJ, LZ and XM contributed to the experiment and interpretation of the data. XM revised the paper. All authors approved the final version of the manuscript.

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Correspondence to Xiaoli Ma.

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All mice experimental procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication, 8th Edition, 2011) and approved by the Ethics Committee of Central Hospital Affiliated to Shandong First Medical University.

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Zhu, P., Kang, G., Jiao, Y. et al. The α5-nAChR/PD-L1 axis facilitates lung adenocarcinoma cell migration and invasion. Human Cell 35, 1207–1218 (2022). https://doi.org/10.1007/s13577-022-00709-1

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