生物信息学和网络药理学分析槲皮素靶向BIRC5抑制胶质母细胞瘤的增殖并影响预后

Quercetin Targeting BIRC5 Inhibits the Proliferation of Glioblastoma and Affects the Prognosis Based on Bioinformatics and Network Pharmacology Analysis

摘要: 目的：本文旨在通过生物信息学和网络药理学方法分析影响胶质母细胞瘤预后关键基因和潜在中药靶点。方法：从基因表达数据库(GEO)获取脑胶质母细胞瘤数据集，GEO2R在线分析得到胶质瘤和正常脑组织之间差异基因。通过Venn图取三个差异基因集交集，共筛选出共有差异基因(DEGs)，并进行GO和KEGG分析富集DEGs的分子功能和信号通路。将差异基因映射入STRING数据库构建蛋白相互作用(PPI)网络，并利用Cytoscape软件筛选Hub基因。GEPIA2数据库分析Hub基因转录表达及预后。TCMSP数据库获取车前子、丹参、金银花、连翘四种中药的生物信息并通过设置药物动力学标准获得活性组分，再通过perl软件从差异基因中获取对应的靶点基因，Cytoscape软件构建“中药成分-DEGs靶点”蛋白质互作网络，分析节点枢纽筛选出关联度较高的靶点基因和活性成分，与Hub基因对比获取最终的潜在关键基因和中药成分，在AutoDock和PyMol软件中进行中药成分和关键基因的分子对接验证。结果：下载得到三个数据库GSE14805、GSE29796、GSE35493，进行GEO2R分析和交集后共得到193个共有的差异表达基因，其中上调基因148个，下调基因45个，并借助Cytoscape软件获取蛋白质互作网络并筛选到15个Hub基因。GO和KEGG分析提示Hub基因主要参与细胞周期、细胞外基质的生物学过程和细胞组分中的细胞粘附连接、粘着斑及胞浆。通过网络药理学分析，建立活性成分–靶点基因相互作用网络后，筛选出潜在的治疗靶点BIRC5和靶向治疗胶质母细胞瘤的中药活性成分槲皮素。分子对接结果显示BIRC5蛋白受体和中药成分配体结合较稳定且有氢键相互作用的形成。结论：通过生物信息学和网络药理学方法分析提示槲皮素有潜在通过靶点BIRC5影响胶质母细胞瘤的增殖、侵袭和迁移，进而影响胶质母细胞瘤患者预后的作用，为胶质瘤治疗和新化疗药的研发提供了新思路。

Abstract: Objective: This study aims to analyze the key genes and potential targets of traditional Chinese medicine that affect the prognosis of glioblastoma through bioinformatics and network pharmacol-ogy methods. Methods: The data set of glioblastoma was obtained from the Gene Expression Omni-bus (GEO), and the differential expressing genes (DEGs) between glioma and normal brain tissue were obtained by online GEO2R analysis. Three sets of differential genes were collected by Venn map, DEGs were screened, and the molecular functions and signal pathways of DEGs were analyzed and enriched by GO and KEGG. The DEGs were mapped into STRING database to construct protein interaction (PPI) network, and the Hub genes were screened by using Cytoscape software. GEPIA2 database was used to analyze the transcriptional expression and prognosis of Hub genes. The bio-logical information of plantain seed, salvia miltiorrhiza, honeysuckle, and forsythia suspensa, and obtains the active components were obtained by setting pharmacokinetic standards. Then, the cor-responding target genes are obtained from the DEGs via perl software. The Cytoscape software con-structs the protein interaction network of “traditional Chinese medicine components-DEGs targets”, and analyzes the node Hub to screen out the target genes and active components with high correla-tion, compare with the Hub genes to obtain the final potential key genes and Chinese medicine in-gredients, and carry out molecular docking verification of Chinese medicine ingredients and key genes in AutoDock and PyMol software. Results: Three databases GSE14805, GSE29796 and GSE35493 were downloaded, and after GEO2R analysis and intersection, 193 common differential expression genes were obtained, including 148 up-regulated genes and 45 down-regulated genes. With the help of Cytoscape software, the protein interaction network was obtained and 15 Hub genes were screened. GO and KEGG analysis indicated that Hub genes were mainly involved in cell cycle, biological process of extracellular matrix and cell adhesion, adhesion spot and cytoplasm in cell components. Through network pharmacological analysis, the potential therapeutic target BIRC5 and the active ingredient quercetin of traditional Chinese medicine targeting the treatment of glioblastoma were screened after the establishment of active ingredient target gene interaction network. The results of molecular docking showed that the binding of BIRC5 protein receptor to the ligand of Chinese traditional medicine was stable and hydrogen bond interaction was formed. Con-clusion: Through the analysis of bioinformatics and network pharmacology methods, it is suggested that quercetin has the potential to affect the proliferation, invasion and migration of glioblastoma through the target BIRC5, thereby affecting the prognosis of glioblastoma patients, providing a new idea for the treatment of glioma and the development of new chemotherapeutic drugs.