基于加权基因共表达网络分析探讨黄芩抗肝细胞癌的相关分子机制

Exploring the Molecular Mechanisms Associated with Scutellaria Baicalensis in the Treatment of Hepatocellular Carcinoma Based on WGCNA

目的 通过网络药理学与加权基因共表达网络分析(Weighted gene co-expression network analysis,WGCNA)相结合的方法,找到黄芩抗肝细胞癌(Hepatocellular carcinoma,HCC)的潜在作用靶点及相关信号通路,探讨其可能的分子作用机制。方法 借助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)筛选黄芩的活性成分及靶点,利用CytoHubba插件获取黄芩前15个候选基因。通过癌症基因组图谱(The cancer genome atlas,TCGA)、基因表达数据库(Gene Expression Omnibus,GEO)下载HCC相关数据,利用R语言与TCGA、GEO的差异基因取交集,对交集基因进行富集分析和hub基因筛选,并进一步对hub基因及黄芩抗HCC潜在基因靶点进行总生存期(Overall survival,OS)、无病生存期(Disease free survival,DFS)分析和人类蛋白组图谱数据库(Human Protein Atlas,HPA)筛选。结果 检索筛选出19种黄芩主要活性成分和50个靶点,候选基因为NCOA1、ESR1、ADRA1A等。得到交集基因115个,经比对黄芩抗HCC的潜在基因靶点为ADRA1A。GO分析显示交集基因富集在体液免疫、补体激活等生物学过程,KEGG分析显示富集在胆固醇代谢、视黄醇代谢等通路。OS、DFS分析显示,FCN3、ADRA1A、C7、COLEC10、CFP这5个基因高表达时更利于患者生存。免疫组化结果显示,与癌旁组织相比,HCC组织中FCN3、C7表达量降低。结论 黄芩抗HCC的分子机制可能与体液免疫、补体激活和细胞凋亡等过程有关,通过靶点ADRA1A干预HCC的发生与转移。FCN3、C7、COLEC10、CFP可作为HCC的核心基因,可能在HCC的治疗中起重要作用,本研究有助于阐明黄芩防治HCC的潜在分子机制。

Objective In this study,network pharmacology and WGCNA were combined to search for potential targets and signaling pathways of scutellaria baicalensis against hepatocellular carcinoma(HCC),and to explore the possible molecular mechanism of action.Methods The active ingredients and targets of Scutellaria baicalensis were screened through the TCMSP database,and the first 15 candidate genes of Scutellaria baicalensis were obtained using the CytoHubba plug-in.The hepatocellular carcinoma(HCC) related data were downloaded through TCGA and GEO databases,and the downloaded data were screened for differential genes and WGCNA modules were constructed using R language.The two modules with the highest positive correlation with normal and HCC samples were selected according to the heat map of clustering module features,and intersected with the differential genes,enrichment analysis of intersection genes and HUB gene screening were carried out,and THE HUB gene and potential anti-HCC gene targets of Scutellaria baicalensis were further screened by OS,DFS and HPA.Results The results showed that a total of 19major active ingredients and 50 targets of Scutellaria baicalensis were obtained,and the candidate genes were NCOA1,ESR1 and ADRA1A.GO analysis showed that the crossover genes were enriched in biological processes such as humoral immunity and complement activation,and KEGG analysis showed that they were enriched in cholesterol metabolism and retinol metabolism,etc.OS and DFS analysis showed that the five genes FCN3,ADRA1A,C7,COLEC10 and CFP were more favorable when they were highly expressed.genes were more favourable for patient survival when highly expressed.Immunohistochemical results showed that the expression of FCN3 and C7 was reduced in HCC tissues compared to paraneoplastic tissues.Conclusion The molecular mechanism of Scutellaria baicalensis against HCC may be related to the processes of humoral immunity,complement activation and apoptosis,interfering with the development and metastasis of HCC through targeting ADRA1A.FCN3,C7,COLEC10 and CFP can be used as the core genes of HCC,they may play an important role in the treatment of HCC,which may help elucidate the underlying molecular mechanism of Scutellaria baicalensis treatment in HCC.