基于红景天苷对三阴性乳腺癌关键差异基因作用机制的生物信息学和分子对接技术分析  

Bioinformatics and molecular docking technology analysis on mechanism of salidroside on key differential genes of triple negative breast cancer

作　　者：朱紫嘉 陈霞[2] 崔曼[3] 文继红[3] 王苹[4] 宋东[1] ZHU Zijia;CHEN Xia;CUI Man;WEN Jihong;WANG Ping;SONG Dong(Department of Breast Surgery,First Hospital,Jilin University,Changchun 130021,China;Department of Pharmacology,School of Basic Medical Sciences,Jilin University,Changchun 130021,China;Department of General Gynecology,First Hospital,Jilin University,Changchun 130021,China;Department of Otorhinolaryngology-Head and Neck Surgery,First Hospital,Jilin University,Changchun 130021,China)

机构地区：[1]吉林大学第一医院乳腺外科,吉林长春130021 [2]吉林大学基础医学院药理学系,吉林长春130021 [3]吉林大学第一医院普通妇一科,吉林长春130021 [4]吉林大学第一医院耳鼻咽喉-头颈外科,吉林长春130021

出　　处：《吉林大学学报（医学版）》2024年第3期759-769,共11页Journal of Jilin University：Medicine Edition

基　　金：吉林省科技厅自然科学基金项目(20210401057YY,20210101326JC)。

摘　　要：目的:通过生物信息学和网络药理学方法探讨红景天苷治疗三阴性乳腺癌(TNBC)的作用机制,阐明其产生治疗作用的主要靶点和信号通路。方法:通过基因表达综合数据库(GEO)获取数据集GSE45827,利用R软件包GSEABase进行基因集富集分析(GSEA),采用limma R软件包寻找相邻正常组织和TNBC组织之间的差异表达基因(DEGs),对DEGs进行基因本体论(GO)功能富集分析和京都基因与基因组百科全书(KEGG)信号通路富集分析,将DEGs与药物靶点结合,导入基因/蛋白相互作用检索搜查工具String数据库,形成蛋白-蛋白相互作用(PPI)网络。使用MCODE插件对PPI网络进行功能模块筛选,对SCORE值排名前2位的关键模块基因再次进行GO功能富集分析和KEGG信号通路富集分析。将2次KEGG富集分析所得通路与转录组数据GSEA富集分析结果取交集,获得红景天苷治疗TNBC的作用通路。使用CytoHubba插件计算出关键模块中最大团中心性(MCC)评分前10位的关键节点基因,即为核心基因。应用AutoDock Vina 1.1.2和PyMOL 2.3.0软件完成分子对接。结果:KEGG与GSEA富集分析的结果取交集得到13条共同通路,涉及细胞周期、细胞衰老和p53信号通路等。GO功能富集分析结果中所涉及的有丝分裂、核分裂和姐妹染色单体分离等生物学过程与细胞周期有密切关联,与KEGG富集分析结果一致。SCORE值排名第1位的关键模块中包含5个红景天苷药物作用靶点,分别为重组人细胞周期蛋白A2(CCNA2)、细胞周期检查点激酶1(CHEK1)、驱动蛋白家族成员11(KIF11)、DNA拓扑异构酶2(TOP2A)和胸腺嘧啶酸合酶(TYMS),将上述蛋白与红景天苷进行分子对接,结果均表现出很强的结合能力(结合能<-7.0 kcal·mol^(-1))。结论:红景天苷的紧密结合靶标位于TNBC的DEGs关键功能模块中,可以与CCNA2蛋白结合产生直接的调控作用,与KIF11、TOPA2、CHEK1和TYMS蛋白结合可针对TNBC的关键节点基因产生间�Objective:To discuss the mechanism of salidroside in the treatment of triple negative breast cancer(TNBC) by using the bioinformatics and network pharmacology methods,and to clarify the main targets and signaling pathways involved in the therapeutic effect.Methods:The dataset GSE45827 was obtained from the Gene Expression Omnibus(GEO) database;the gene set enrichment analysis(GSEA) was performed by using the R software package GSEABase;the differentially expressed genes(DEGs) between the adjacent normal tissue and TNBC tissue were identified by limma R software package;the Gene Ontology(GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) signaling pathway enrichment analysis were performed on the DEGs,and the DEGs were integrated with the drug targets to import into gene/protein interaction retrieval tool String database,and the protein-protein interaction(PPI) networks were constructed;the functional module screening of the PPI network was conducted by MCODE plugin,and the top 2 modules ranked by SCORE value were further subjected to GO functional enrichment analysis and KEGG signaling pathway analysis.The pathways obtained from the two rounds of KEGG enrichment analysis were intersected with the results of GSEA enrichment analysis to identify the pathways involved in the therapeutic effect of salidroside on TNBC.The top 10 key node genes in the highest scoring module determined by the maximum clique centrality(MCC) score caculated by CytoHubba plugi were considered as the core genes;the molecular docking was performed by AutoDock Vina1.1.2 and PyMOL2.3.0 Software.Results:The intersection of KEGG and GSEA enrichment analysis results showed 13 singaling pathways,including the cell cycle,cellular senescence,and p53 signaling pathways,and so on.The biological processes involved in the GO functional analysis,such as mitosis,nuclear division,and sister chromatid separation,were closely related to the cell cycle and consistented with the results of the KEGG signaling pathway enrichment

关 键 词：红景天苷 三阴性乳腺癌 生物信息学 网络药理学 分子对接 

分 类 号：R737.9[医药卫生—肿瘤] R285.5[医药卫生—临床医学]