基于网络药理学鸡血藤治疗肝细胞癌的作用机制研究

Network pharmacology-based study on mechanism of Spatholobus suberectus Dunn treating hepatocellular carcinoma

目的采用网络药理学研究方法探索鸡血藤的有效成分治疗肝细胞癌的作用机制。方法利用中药系统药理学数据库与分析平台筛选鸡血藤口服生物利用度≥30%及类药性≥0.18的有效成分,采用Perl软件预测有效成分的作用靶标。采用GeneCards数据库及OMIM数据库筛选肝细胞癌疾病靶标。将鸡血藤有效成分作用靶标及肝细胞癌疾病靶标取交集后得到中药-疾病共同靶标,采用Cytoscape软件构建中药-成分-疾病-靶标调控网络,并构建中药-疾病靶标的蛋白互作网络及条形图,并筛选出核心靶标。对核心靶标进行功能富集分析与通路富集分析。结果鸡血藤主要通过22种有效成分作用于46个中药-疾病共同靶标,其治疗肝细胞癌的核心基因有EGFR、MYC、Caspase3、cyclinD1、IL-6、VEGFA、ERBB2、ESR1、MDM2、Caspase8等。核心基因涉及的功能主要包括类固醇激素受体活性、半胱氨酸型内肽酶活性参与凋亡过程、泛素样蛋白连接酶结合、核受体活性、转录因子活性、直接的配体调节序列特异性DNA结合、泛素蛋白连接酶结合、核激素受体结合等;涉及的通路主要包括前列腺癌信息通路、人巨细胞病毒感染信号通路、乙型病毒性肝炎信号通路、卡波西氏肉瘤相关疱疹病毒感染信号通路、EB病毒感染信号通路、膀胱癌信号通路、糖尿病并发症中的AGE-RAGE信号通路、p53信号通路、铂耐药信号通路、乳腺癌信号通路、癌症中的微小RNA信号通路、丙型病毒性肝炎信号通路、甲状腺激素信号通路等。结论鸡血藤的主要有效成分通过调控肝细胞癌的相关基因,影响乙型/丙型病毒性肝炎、人巨细胞病毒/EB病毒感染、糖尿病等多种信号通路,从而发挥治疗肝细胞癌的作用。

Objective To explore the mechanism of active ingredients of Spatholobus suberectus Dunn treating hepatocellular carcinoma(HCC)using the method of network pharmacological study.Methods The active ingredients of Spatholobus suberectus Dunn were screened through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform according to oral bioavailability≥30%and drug-likeness≥0.18,the targets of active ingredients were predicted by using Perl software.GeneCards database and OMIM database were employed to screen the targets of hepatocellular carcinoma diseases.Common targets of Chinese medicine-disease were obtained after conducting intersection between the targets of active ingredients of Spatholobus suberectus Dunn and HCC-related targets,then the regulatory network of Chinese medicine-ingredients-disease-targets was constructed using Cytoscape software;besides,protein-protein interaction network and bar graph of Chinese medicine-disease targets were established,then the core targets were screened.Function and pathways enrichment analysis were performed on the core targets.Results Spatholobus suberectus Dunn acted on 46 common targets of Chinese medicine-disease mainly by 22 active ingredients,and the core genes treating HCC included EGFR,MYC,Caspase3,cyclinD1,IL-6,VEGFA,ERBB2,ESR1,MDM2 and Caspase8,etc.The functions of the core genes mainly included steroid hormones receptor activity,cysteine-type endopeptidase activity involved in apoptosis process,ubiquitin-like protein ligase binding,nuclear receptor activity,transcription factor activity,direct ligand regulated sequence-specific DNA binding,ubiquitin protein ligase binding and nuclear hormone receptor binding,ect.;the pathways involved mainly included prostate cancer signaling pathway,human cytomegalovirus infection signaling pathway,hepatitis B signaling pathway,Kaposi sarcoma-associated herpesvirus infection signaling pathway,EB virus infection signaling pathway,bladder cancer signaling pathway,AGE-RAGE signaling pathway in diabetic complications,p53 signaling pathway,platinum drug resistance signaling pathway,breast cancer signaling pathway,microRNA signaling pathway in cancer,hepatitis C signaling pathway and thyroid hormone signaling pathway,etc.Conclusion The main active ingredients of Spatholobus suberectus Dunn affect multiple signaling pathways by modulating HCC-related genes,including hepatitis B/C,human cytomegalovirus/EB virus infection,and diabetes signaling pathways,thus exerting an therapeutic effect on HCC.