α5-nAChR/NETO2 contributed to chronic stress-promoted lung adenocarcinoma progression.

IF 5.3 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-02-25 DOI:10.1186/s12935-025-03701-5

Jingting Wang, Jiaying Cai, Zengping Wang, Shuran Yang, Jing Wang, Yanfei Jia, Haiji Sun, Xiaoli Ma

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引用次数: 0

Abstract

Background: α5-nicotinic acetylcholine receptor (α5-nAChR) participates in chronic stress-promoted lung adenocarcinoma (LUAD) progression. Neuropilin and tolloid-like 2 (NETO2) contributes to fear expression and extinction, which is related to tumorigenesis. CHRNA5 (encoding α5-nAChR) gene profiling revealed a reduction in NETO2 expression following CHRNA5 knockdown. Nevertheless, the connection between α5-nAChR and NETO2 in LUAD progression induced by chronic stress remains unclear.

Methods: RNA-Seq and bioinformatics database were used for analyzing the expression as well as correlation of α5-nAChR, together with NETO2 in LUAD. α5-nAChR and NETO2 expression were detected using immunohistochemistry in LUAD tissue microarrays, chronic restraint stress (CRS) and chronic unpredictable stress (CUMS) mice tissues. In lung adenocarcinoma A549 and H1299 cells, the expression of α5-nAChR, NETO2, p-CAMKII, p-STAT3 and vimentin induced by acetylcholine/nicotine was examined by western blot. The interaction of α5-nAChR with NETO2 in lung adenocarcinoma cells was detected by Co-immunoprecipitation assay and modeled using molecular docking. EdU assay and colony formation assay were conducted to evaluate cell proliferation, while wound healing assay as well as transwell assay assessed the migration and invasion of lung adenocarcinoma cells.

Results: α5-nAChR expression was related to NETO2 expression, low survival rate, staging as well as smoking status in LUAD dataset as well as tissue microarrays. The correlation between α5-nAChR and NETO2 was validated in nude mice xenograft tissues. α5-nAChR as well as NETO2 expression correlated in CRS and CUMS mice tissues. In vitro, acetylcholine/nicotine mediated NETO2, p-CAMKII, p-STAT3 and vimentin expression via α5-nAChR. α5-nAChR interacted with NETO2 as well as CAMKII in LUAD cells. α5-nAChR/NETO2 signaling contributed to LUAD cell proliferation, migration and invasion.

Conclusions: The above results uncover a new chronic stress-promoted LUAD signaling pathway: α5-nAChR/NETO2 axis contributes to chronic stress-promoted LUAD cell proliferation, migration and invasion.

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α5-nAChR/NETO2参与慢性应激促进的肺腺癌进展。

背景：α5-烟碱乙酰胆碱受体（α5-nAChR）参与慢性应激促进肺腺癌（LUAD）的进展。Neuropilin和tolloloid - 2 （NETO2）参与恐惧的表达和消除，这与肿瘤发生有关。CHRNA5（编码α5-nAChR）基因分析显示，在CHRNA5基因敲低后，NETO2的表达减少。然而，α5-nAChR与NETO2在慢性应激诱导的LUAD进展中的关系尚不清楚。方法：采用RNA-Seq和生物信息学数据库分析α5-nAChR、NETO2在LUAD中的表达及其相关性。采用免疫组化方法检测LUAD组织芯片、慢性限制性应激（CRS）和慢性不可预测应激（CUMS）小鼠组织中α5-nAChR和NETO2的表达。采用western blot法检测乙酰胆碱/尼古丁诱导的肺腺癌A549、H1299细胞α - 5- nachr、NETO2、p-CAMKII、p-STAT3、vimentin的表达。采用共免疫沉淀法检测肺腺癌细胞中α5-nAChR与NETO2的相互作用，并采用分子对接方法建立模型。用EdU法和集落形成法评估细胞增殖，用伤口愈合法和transwell法评估肺腺癌细胞的迁移和侵袭。结果：α5-nAChR表达与NETO2表达、低生存率、分期、吸烟状况相关。α5-nAChR与NETO2在裸鼠异种移植组织中的相关性得到验证。α5-nAChR与NETO2在CRS和CUMS小鼠组织中的表达相关。体外，乙酰胆碱/尼古丁通过α5-nAChR介导NETO2、p-CAMKII、p-STAT3和vimentin的表达。α5-nAChR在LUAD细胞中与NETO2和CAMKII相互作用。α5-nAChR/NETO2信号通路参与LUAD细胞的增殖、迁移和侵袭。结论：上述结果揭示了一种新的慢性应激促进LUAD信号通路：α5-nAChR/NETO2轴参与慢性应激促进LUAD细胞的增殖、迁移和侵袭。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

CiteScore

10.90

自引率

1.70%

发文量

360

审稿时长

1 months

期刊介绍： Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.