摘要
目的 鉴定大黄牡丹汤治疗结肠癌的核心化合物和靶点,以及构建预后模型来评估患者的总体生存情况。方法 通过检索多个数据库筛选得到大黄牡丹汤治疗结肠癌的靶点;通过GO和KEGG富集分析探讨大黄牡丹汤治疗结肠癌的作用机制;在使用单因素Cox分析筛选出与生存相关的靶点后,使用LASSO回归构建预后模型,计算模型风险评分;KM生存分析和ROC曲线用以验证和评估模型的可靠性;构建蛋白互作(proteinproteininteraction,PPI)网络和疾病-药物-化合物-靶点网络以筛选出核心靶点;使用HPA免疫组化数据库和Image J软件对核心靶点进行蛋白表达的验证;分子对接和分子动力学以评估核心化合物和靶点的结合情况。结果 共筛选出22个大黄牡丹汤治疗结肠癌的靶点,其主要参与调控对酮、氧水平的反应等生物学过程,与胃泌素信号、DNA损伤应答通路有关。LASSO回归去除冗杂因素,对单因素Cox分析筛选出的5个基因(CHEK1、BIRC5、GSTM2、CCNB1、VEGFA)构建预后模型。疾病-药物-化合物-靶点网络共筛选出2个核心化合物:槲皮素和芦荟大黄素。PPI网络共筛选出4个核心靶点:CCNB1、MYC、CCND1、PCNA。将核心靶点和预后模型的基因取交集,得到核心的1个靶点:CCNB1。生存分析显示CCNB1在高低风险组之间具有显著性差异。免疫组化结果表明,CCNB1在正常组织和结肠癌组织中差异表达,其差异具有统计学意义(P<0.01)。分子对接和分子动力学结果验证了芦荟大黄素、槲皮素和CCNB1具有稳定的结合能。结论 大黄牡丹汤治疗结肠癌发挥作用主要可能通过槲皮素、芦荟大黄素靶向CCNB1来实现,大黄牡丹汤治疗结肠癌的预后模型可以用于患者预后的评估,效能良好。
OBJECTIVE To identify the core compounds and targets of Dahuang-Mudan decoction for colon cancer,and construct a prognostic model to evaluate the overall survival of patients.METHODS Targets of Dahuang-Mudan decoction for colon cancer were screened from multiple databases.GO analysis and KEGG pathway enrichment analysis were performed to explore the possible mechanisms of targets.After screening for survival-related targets by univariate Cox analysis,LASSO regression were used to construct a prognostic model and calculate the scores of the model.KM survival analysis and ROC curve were adopted to verify and evaluate the model’s feasibility.Protein protein interaction(PPI) network and Disease-DrugCompound-Target network were constructed to screen the core target.HPA immunohistochemistry database and Image J software were employed to demonstrate the protein expression of the core target.Molecular docking and dynamics were evaluated to the binding activity of the core compounds and targets.RESULTS A total of 22 targets in Dahuang-Mudan decoction for colon cancer had been screened.These targets participated in regulating ketone and oxygen level rea ction and were related to gastrin signaling and DNA injury response pathway.After removing the redundant factors,five genes including CHEK1,BIRC5,GSTM2,CCNB1 and VEGFA,which were screened by univariate Cox analysis,were used to construct a model by LASSO regression.
作者
张泽鑫
林思其
刘紫凤
吴汶丰
黄子怡
陈祎琦
李菁
林丽珠
于奕
ZHANG Zexin;LIN Siqi;LIU Zifeng;WU Wenfeng;HUANG Ziyi;CHEN Yiqi;LI Jing;LIN Lizhu;YU Yi(Guangzhou University of Chinese Medicine,The First Clinical Medical College,Guangzhou 510405,China;Guangzhou University of Chinese Medicine,The Second Clinical Medical College,Guangzhou 510405,China;The First Hospital of Hunan University of Chinese Medicine,Changsha 410000,China;The First Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510405,China)
出处
《中国现代应用药学》
CAS
CSCD
北大核心
2022年第15期1925-1937,共13页
Chinese Journal of Modern Applied Pharmacy
基金
湖南省卫生健康委2020年度科研立项课题(20200949)。
关键词
分子对接
分子动力学
免疫组化
大黄牡丹汤
结肠癌
预后模型
molecular docking
molecular dynamics
immunocytochemistry
Dahuang-Mudan decoction
colon cancer
prognostic model