SNAP25诱导的MYC上调促进高等级神经内分泌肺癌的进展

SNAP25-induced MYC upregulation promotes high-grade neuroendocrine lung carcinoma progression

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Frontiers in Immunology

影响因子:5.9

分区:医学2区 / 免疫学2区

发表日期:2024

作者: Zhiqiang Chen, Shujing Wang, Jingrui Wang, Ying Wang, Xiangjun Qi, Bo An, Lingling Sun, Lizhu Lin

DOI: 10.3389/fimmu.2024.1411114

摘要

本研究探讨了突触体相关蛋白25（SNAP25）在高等级神经内分泌癌（HGNEC）中的表达及作用。我们通过差异表达分析和加权基因共表达网络分析（WGCNA）筛选出HGNEC中的关键基因和模块。KEGG和GO分析帮助理解这些基因的功能，ROC曲线评估其诊断价值。我们还研究了SNAP25与免疫浸润的关系，并通过体外、体内实验及数据集验证了相关发现。WGCNA识别了595个与MAPK信号通路、GABA能突触及癌相关转录调控异常等相关的关键基因，主要包括SNAP25、MYC、NRXN1、GAD2和SYT1。SNAP25与M2巨噬细胞浸润显著相关。GSE40275数据集证实SNAP25在HGNEC中的高表达与预后不良。qRT-PCR和免疫印迹分析显示，HGNEC中SNAP25和c-MYC水平升高，促进MEK/ERK通路的活性。敲低SNAP25可减弱H1299细胞的增殖、迁移和侵袭能力，同时降低c-MYC、MEK和ERK的水平。体内实验进一步确认SNAP25敲除可抑制肿瘤生长。SNAP25通过刺激MEK/ERK通路调控c-MYC的激活，最终影响HGNEC的发展。

Abstract

This study investigated the expression and role of Synaptosome associated protein 25 (SNAP25) in high-grade neuroendocrine carcinoma (HGNEC).We used differentially expressed analysis and weighted gene co-expression network analysis (WGCNA) to identify key genes and modules in HGNEC. KEGG and GO analyses helped understand these genes' roles, and ROC curves assessed their diagnostic value. We also studied SNAP25's relation to immune infiltration and confirmed findings with in vitro and vivo experiments and datasets.WGCNA identified 595 key genes related to pathways like MAPK signaling, GABAergic synapse, and cancer-related transcriptional misregulation. Top genes included SNAP25, MYC, NRXN1, GAD2, and SYT1. SNAP25 was notably associated with M2 macrophage infiltration. Dataset GSE40275 confirmed SNAP25's high expression and poor prognosis in HGNEC. qRT-PCR and WB analyses showed increased SNAP25 and c-MYC levels in HGNEC, promoting MEK/ERK pathway activity. Reducing SNAP25 decreased H1299 cell proliferation, migration, invasion, and levels of c-MYC, MEK, and ERK. Finally, in vivo experiments further confirmed that SNAP25 knockout can inhibit tumor growth.SNAP25 regulates c-MYC activation by stimulating the MEK/ERK pathway, ultimately influencing the development of HGNEC.