Background: Chronic nicotine exposure drives head and neck cancer (HNC) progression, yet its molecular mechanisms remain underexplored. This study examines nicotine-induced transcriptomic changes and potential therapies via drug repurposing.Methods: HNC cell lines (OECM1, SAS, and CGHNC9) were exposed to an IC30 nicotine dose for three months to model chronic exposure in habitual smokers. Transcriptomic profiling of these sublines was integrated with TCGA-HNSC patient data. Differentially expressed genes (DEGs) underwent functional pathway enrichment analysis. Drug repurposing was conducted using gene–drug correlation analysis across GDSC, CTRP, and PRISM databases.Results: Transcriptomic analysis identified 1223 DEGs in nicotine-exposed HNC cells, and integration with TCGA-HNSC data defined a Nic-HNC gene set of 168 genes: 149 oncogenes and 19 tumor suppressors, with 36 oncogenes overexpressed in heavy smokers. Pathway analysis revealed the upregulation of oncogenic signaling, such as PI3K-AKT, alongside the suppression of immune regulation and metabolic reprogramming. Drug repurposing identified five compounds—AZD1332, JAK-8517, NU7441, BRD-K30748066, and neopeltolide—with the first two exhibiting the strongest inverse correlations with nicotine-induced oncogenes in heavy smokers, highlighting their potential as targeted therapies for tobacco-associated HNC.Conclusions: This study comprehensively characterizes nicotine-driven molecular dysregulation in HNC and proposes AZD1332 and JAK-8517 as promising therapeutic candidates through drug repurposing. These insights advance our understanding of nicotine’s oncogenic role and provide a foundation for translational research to develop targeted interventions for tobacco-associated HNC.
背景：长期尼古丁暴露会驱动头颈癌（HNC）进展，但其分子机制仍未得到充分研究。本研究通过药物重定位策略，探讨尼古丁诱导的转录组学变化及潜在治疗方法。 方法：将HNC细胞系（OECM1、SAS和CGHNC9）暴露于IC30剂量尼古丁三个月，模拟习惯性吸烟者的慢性暴露状态。对这些亚系进行转录组学分析，并与TCGA-HNSC患者数据整合。对差异表达基因（DEGs）进行功能通路富集分析。通过GDSC、CTRP和PRISM数据库的基因-药物相关性分析进行药物重定位研究。 结果：转录组学分析在尼古丁暴露的HNC细胞中鉴定出1223个DEGs，与TCGA-HNSC数据整合后确定了包含168个基因的Nic-HNC基因集：其中149个为致癌基因，19个为抑癌基因，其中36个致癌基因在重度吸烟者中过表达。通路分析显示致癌信号（如PI3K-AKT通路）上调，同时免疫调节和代谢重编程受到抑制。药物重定位筛选出五种化合物——AZD1332、JAK-8517、NU7441、BRD-K30748066和新佩托内酯，其中前两种化合物与重度吸烟者尼古丁诱导的致癌基因呈最强负相关，凸显了其作为烟草相关HNC靶向治疗的潜力。 结论：本研究系统阐明了尼古丁驱动HNC分子失调的特征，并通过药物重定位提出AZD1332和JAK-8517作为有前景的治疗候选药物。这些发现深化了对尼古丁致癌作用的理解，为开展转化研究、开发烟草相关HNC的靶向干预措施奠定了基础。
肿瘤(癌症)患者之家