结直肠癌中缺氧诱导的EGFR抑制剂耐药相关基因的鉴定和机制研究OA
Identification and mechanism of genes associated with hypoxia-induced resistance to EGFR inhibitors in colorectal cancer
目的 通过生物信息学分析结合实验验证,筛选和探讨提高结直肠癌中表皮生长因子受体(EGFR)抑制剂疗效的基因及其潜在机制.方法 从TCGA数据库下载结直肠癌RNA-Seq数据与临床数据,从GeneCards数据库获取缺氧相关基因(HRGs).对HRGs进行京都基因和基因组数据库富集分析.通过加权基因共表达网络分析(WGCNA)筛选出与结直肠癌相关的基因模块,使用单因素Cox、LASSO以及多因素Cox回归构建预后模型.蛋白质-蛋白质相互作用网络分析、筛选与EGFR抑制剂耐药相关的关键基因.通过Kaplan-Meier Plotter和UALCAN数据库验证模型基因及关键基因与结直肠癌预后的相关性.采用ShinyGO(0.80)数据库分析这些基因的通路富集情况.利用GEO数据库、定量聚合酶链反应实验及单细胞测序分析BCL2L1的临床价值.结果 HRGs基因显著富集于HIF-1信号通路、PI3K/Akt和EGFR抑制剂耐药性等多个信号通路.WGCNA分析得到196个特征模块基因,并建立由8个基因组成的结直肠癌预后模型,蛋白质-蛋白质相互作用网络筛选出10个关键基因.预后分析显示,这些基因的表达水平与结直肠癌的预后显著相关.BCL2L1在耐药组和癌组织中的表达水平较高(P<0.05).结论 建立的包含8个基因的模型,可以较好地预测结直肠癌患者的预后.在缺氧条件下,BCL2L1对结直肠癌EGFR抑制剂耐药性的调控发挥了关键作用.
Objective To identify genes,via a bioinformatics analysis,that enhance the therapeutic efficacy of epidermal growth factor receptor(EGFR)inhibitors in colorectal cancer,as well as their potential mechanisms.Methods RNA-Seq data and clinical data for colorectal cancer were obtained from the TCGA database,while hypoxia-associated genes(HRGs)were acquired from the GeneCards database.Kyoto Encyclopedia of Genes and Genomes enrichment analysis was conducted on HRGs to identify potential enrichment pathways.Gene modules associated with colorectal cancer were identified using weighted gene coexpression network analysis(WGCNA),and prognostic models were constructed using univariate Cox regression,LASSO,and multivari-ate Cox regression.Protein-protein interaction network analysis was performed to identify key genes associat-ed with EGFR inhibitor resistance.Subsequently,the Kaplan-Meier Plotter and UALCAN databases were uti-lized to validate the relationship between the model genes,key genes,and colorectal cancer prognosis.The pathway enrichment of these genes was analyzed using the ShinyGO(0.80)database.The clinical value of BCL2L1 was analyzed by GEO database,quantitative polymerase chain reaction and single cell sequencing.Results The HRGs were found to be significantly enriched in the HF-1 signaling pathway,as well as in PI3K/Akt and EGFR inhibitor resistance.WGCNA analysis identified 166 characteristic module genes and estab-lished a prognostic model for colorectal cancer composed of 8 genes,while the protein-protein interaction net-work analysis identified 10 key genes.The prognostic analysis revealed a significant correlation between the expression levels of these genes and the prognosis of colorectal cancer.Furthermore,the expression level of BCL2L1 was significantly higher in the drug-resistant group(P<0.05).Conclusions A model comprising 8 genes was developed to predict the prognosis of patients with colorectal cancer.BCL2L1 plays a crucial role in regulating resistance to EGFR inhibitors in colorectal cancer under hypoxic conditions.
李桐桐;刘涛;黄翌楚;余春燕;姜雷
兰州大学 第一临床医学院,甘肃 兰州 730000兰州大学 第一临床医学院,甘肃 兰州 730000兰州大学 第一临床医学院,甘肃 兰州 730000兰州大学 第一临床医学院,甘肃 兰州 730000兰州大学第一医院 普外科,甘肃 兰州 730000
临床医学
结直肠癌耐药缺氧表皮生长因子受体单细胞测序分析
colorectal carcinomaresistancehypoxiaepidermal growth factor receptorsingle cell sequenc-ing analysis
《兰州大学学报（医学版）》 2025 (9)
8-17,10
国家自然科学基金资助项目(82060527)
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