基于WGCNA联合网络药理学探讨益髓生血胶囊治疗肝细胞癌的分子机制  

Molecular Mechanism of Benefiting-marrow Generating-blood Capsules in the Treatment of Hepatocellular Carcinoma Based on WGCNA and Network Pharmacology

作　　者：李高勤 张志明 颉志英 苏欢 张欣 张卫强 黄达 李娟 雍文兴 LI Gaoqin;ZHANG Zhiming;JIE Zhiying;SU Huan;ZHANG Xin;ZHANG Weiqiang;HUANG Da;LI Juan;YONG Wenxing(Affiliated Hospital of Gansu University of Chinese Medicine,Lanzhou 730000,China;Gansu Provincial Hospital of Traditional Chinese Medicine,Lanzhou 730050,China)

机构地区：[1]甘肃中医药大学附属医院,甘肃兰州730000 [2]甘肃省中医院,甘肃兰州730050

出　　处：《西部中医药》2024年第10期56-63,共8页Western Journal of Traditional Chinese Medicine

基　　金：国家自然科学基金地区基金(81660730);甘肃省中西医结合肿瘤临床医学研究中心项目(18JR2FA001)。

摘　　要：目的:基于加权基因共表达网络分析(weighted gene co-expression network analysis,WGCNA)联合网络药理学方法探讨益髓生血胶囊治疗肝细胞癌(hepatocellular carcinoma,HCC)的分子机制,筛选肝细胞癌潜在预后标志物。方法:采用中药系统药理学数据库与分析平台(traditional Chinese medicine systems pharmacology database and analysis platform,TCMSP)筛选益髓生血胶囊有效成分对应靶点;从TCGA数据库下载HCC及癌旁组织基因芯片,通过“Limma”包筛选差异基因;使用WGCNA包通过TCGA数据库中HCC的基因表达数据图谱构建基因共表达网络,筛选与临床性状相关基因模块;对益髓生血胶囊调控基因、HCC差异基因、模块基因取交集;使用Cytoscape构建药物-靶点-疾病网络,对交集基因进行基因本体论(gene ontology,Go)和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析;使用STRING数据库构建交集基因间的蛋白-蛋白互作(protein-protein interactions,PPI)网络;根据最大团中心性(maximal clique centrality,MCC)评分对前10个基因与HCC的预后进行探索,进一步分析以获得HCC潜在标志物。结果:共获得益髓生血胶囊438个有效成分对应靶点;从TCGA数据库共获得374个肿瘤样本和50个正常样本,Limma包共筛选出2703个差异基因;WGCNA筛选出1922个与正常组织相关的基因,交集基因共26个,主要富集于细胞衰老、细胞周期、乙肝、p53信号通路、多种癌症、IL-17等信号通路;26个交集基因中,7个基因的高表达与肝癌患者的较差总生存率(overall survival,OS)/无病生存率(disease free survival,DFS)具有显著差异(P<0.05)。结论:益髓生血胶囊治疗HCC的作用机制复杂,主要涉及细胞衰老、细胞周期、乙肝、p53信号通路、多种癌症、IL-17等信号通路,其主要作用成分可能与榭皮素、木草素、芦荟大黄素、芒柄花素等有关。BIRC5、CCNA2、CCNB1、CDK1、CHEK1、E2F1、TOP2A等7Objective:To discuss molecular mechanism of Yisui Shengxue(Benefiting-marrow Generatingblood)capsules in the treatment of hepatocellular carcinoma on the foundation of weighted gene co-expression network analysis(WGCNA)and network pharmacology,and to screen for potential prognostic markers in hepatocellular carcinoma.Methods:TCMSP was adopted to screen the corresponding targets of the active ingredients of the capsules;the gene chips of hepatocellular carcinoma and paraneoplastic tissue were downloaded from TCGA database,and the differential genes were screened from Limma package;the WGCNA package was used to construct the gene co-expression network for the gene expression data map of hepatocellular carcinoma in TCGA database,and screen the gene modules related to clinical traits;the intersection of benefiting-marrow generatingblood capsules regulatory genes,hepatocellular carcinoma differential genes and module genes were taken to construct the internet of drug-target-disease by Cytoscape,GO and KEGG pathway enrichment analysis of the intersected genes were conducted;STRING database was adopted to construct protein-protein interactions(PPI)network;the top ten genes and the prognosis of hepatocellular carcinoma were surveyed according to maximal clique centrality(MCC)scales,in order to obtain the potential markers of hepatocellular carcinoma by further analysis.Results:The analysis has yielded 438 corresponding targets of active ingredients of the capsules;374 tumor samples and 50 normal samples were obtained from TCGA database,and 2703 differential genes were gained from Limma package;1922 genes related to normal tissues and 26 intersected genes were screened by WGCNA,mainly concentrated in cell senescence,cell cycle,hepatitis B,p53 signaling pathway,many kinds of cancer,IL-17 and other signling pathways;among the 26 intersection genes,the significant differences existed between the high expression of seven genes and the poor overall survival(OS)/disease free survival(DFS)in patients with liver cancer(P<0.05).Co

关 键 词：肝细胞癌 网络药理学 WGCNA 益髓生血胶囊 

分 类 号：R285[医药卫生—中药学]