基于网络药理学和生物信息学探究黄芪四君子汤治疗肝细胞癌的作用机制

Explore the Mechanism of Huangqi Sijunzi Decoction in the Treatment of Hepatocellular Carcinoma Based on Network Pharma⁃cology and Bioinformatics

[目的]运用网络药理学联合生物信息学方法,探究黄芪四君子汤治疗肝细胞癌(hepatocelluar carcinoma,HCC)的潜在作用机制。[方法]利用中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)数据库对中药的生物活性成分及其靶点进行鉴定。采用差异分析和加权基因共表达网络分析(weighted gene coexpression net work analysis,WGCNA)鉴定HCC的差异基因和模块基因,在此基础上构建中药成分-靶点网络。随后研究靶点的生物学功能,并构建蛋白互作(protein-protein interaction,PPI)网络,识别药物治疗HCC的关键靶点。最后通过分子对接探索化合物与靶点之间的相互作用。[结果]共鉴定出5种草药的156种化合物和227个靶点,癌症基因组图谱(The Cancer Genome Atlas,TCGA)和基因表达综合(Gene Expression Omnibus,GEO)数据库数据集中差异基因2477和685个,WGCNA关联模块基因2104和2165个。构建了包含4种草药、85种化合物和9个靶点的中药成分-靶点网络。生物功能分析表明,9个靶点主要与细胞周期、p53信号通路、细胞衰老相关,筛选出山柰酚、槲皮素2个药物主要成分和细胞周期蛋白A2(cyclin A2,CCNA2)、雌激素受体1(estrogen receptor alpha,ESR1)、细胞周期蛋白B1(cyclin B1,CCNB1)、细胞周期蛋白依赖性激酶1(cyclin-dependent kinase 1,CDK1)、拓扑异构酶Ⅱα(topoisomeraseⅡalpha,TOP2A)5个核心靶点。分子对接结果显示,山柰酚、槲皮素与对应的核心靶点具有稳定的结合能力。[结论]黄芪四君子汤可能通过调节细胞周期蛋白以及相关通路发挥对HCC的治疗作用,本研究为黄芪四君子汤治疗HCC提供了研究思路和理论支撑。

[Objective]To explore the potential mechanism of action of Huangqi Sijunzi Decoction in the treatment of hepatocellular carcinoma(HCC)by network pharmacology combined with bioinformatics methods.[Methods]The bioactive compounds of drugs and their targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)database.Differential gene and module gene of HCC were identified by differential analysis and weighted gene co-expression network analysis(WGCNA).On this basis,the network of“Components-targets of Chinese drug”was constructed.Subsequently,the biological function of the target was investigated and protein-protein interaction(PPI)network was constructed to identify key targets for drug therapy of HCC.Finally,the interaction between the target and the compound was explored by molecular docking.[Results]A total of 156 compounds and 227 targets of 5 Chinese drugs were identified,as well as 2477 and 685 differential genes in The Cancer Genome Atlas(TCGA)and Gene Expression Omnibus(GEO)datasets,and 2104 and 2165 WGCNA association module genes.Then,the Chinese drug component-target network containing 4 drugs,85 compounds and 9 targets was constructed.Biological function analysis showed that the 9 targets were mainly related to cell cycle,p53 signaling pathway and cell senescence.Meanwhile,two core components of kaempferol and quercetin and five core targets of cyclin A2(CCNA2),estrogen receptor alpha(ESR1),cyclin B1(CCNB1),cyclin-dependent kinase 1(CDK1)and topoisomeraseⅡalpha(TOP2A)were screened.Molecular docking results showed that the kaempferol and quercetin had stable binding ability to the corresponding core targets.[Conclusion]Huangqi Sijunzi Decoction may play a therapeutic role in HCC by regulating pathways and proteins related with cell cycle.This study provides research ideas and theoretical support for the treatment of HCC with Huangqi Sijunzi Decoction.