摘要
目的:基于网络药理学、临床数据生物信息学及分子对接探讨红景天苷调控胃癌的铁死亡机制。方法:借助Symmap和UniProt数据库检索获得红景天苷的药物靶点,通过ferrDb数据库获得铁死亡相关基因,利用GeneCards、OMIM、TTD等数据库获得胃癌相关疾病靶点,Cytoscape 3.9.1软件构建“成分-靶点”网络,STRING数据库及Cytoscape构建蛋白质相互作用(protein-protein interaction,PPI)网络。借助数据库UALCAN分析红景天苷靶向铁死亡核心基因的转录水平,Kaplan-Meier plotter分析核心基因表达与患者生存之间的关系。通过DAVID数据库进行基因本体论(gene ontology,GO)功能和京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路富集分析。采用RCSB与AutoDock Vina 1.1.2软件完成红景天苷与核心基因的分子对接,验证其与靶点基因的结合活性。结果:红景天苷靶向基因60个,其中铁死亡基因20个;DDIT3、GSK3B、HIF1A、MAPK1、MTOR(FRAP)、PARP1、PIK3CA、RELA(NFKB3)、SIRT1、VEGFA、PRKAA1、MAPK3、PRKAA2基因mRNA在胃癌组织中异常表达(P<0.05),其中DDIT3、MAPK3、VEGFA、PRKAA2、RELA(NFKB3)、HIF1A、MAPK1、PIK3CA、SIRT1、PRKAA1、PARP1 mRNA异常表达与胃癌患者预后相关(P<0.05);GO分析主要富集于细胞分裂、细胞增殖、凋亡等调控,KEGG分析主要富集于PI3K-Akt、HIF-1、FoxO等信号通路、凋亡、自噬、卡波西肉瘤相关疱疹病毒感染、活性氧化学致癌、癌症通路、肿瘤中PD-L1表达和PD-1检查点通路及长寿调节通路等。分子对接结果显示红景天苷与PARP1、PRKAA1、HIF1A、MAPK1、RELA(NFKB3)、MAPK3、PIK3CA均有强烈的结合活性(分数<-6.0),与PRKAA2、SIRT1、VEGFA、DDIT3具有较好的结合活性(-6.0<分数<-4.0)。结论:红景天苷调控胃癌的铁死亡机制具有多靶点、多途径的协同作用特点,主要作用于DDIT3、MAPK3、VEGFA、PRKAA2、RELA(NFKB3)、HIF1A、MAPK1、PIK3CA、SIRT1、PRKAA1、PARP1靶�
Objective:To investigate the Salidroside-regulated ferroptosis mechanism in gastric cancer using molecular docking,network pharmacology,and clinical data bioinformatics.Methods:The drug targets for Salidroside were sourced from the Symmap and UniProt databases;the genes related to ferroptosis were sourced from the ferrDb database;the disease targets for gastric cancer were sourced from the GeneCards,OMIM,and TTD databases,Cytoscape 3.9.1 software was utilized to construct the component-target network,and Cytoscape and the STRING database were utilized to construct the protein-protein interaction(PPI)network.Using the Kaplan-Meier plotter to examine the correlation between core gene expression and patient survival,and the database UALCAN to assess the transcript levels of the core gene for Salidroside-targeted ferroptosis.Gene ontology(GO)function and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis were performed using the DAVID database.RCSB and AutoDock Vina 1.1.2 software were used to complete the molecular docking of Salidroside with the core genes and to validate their binding activities with the target genes.Results:There were 60 genes that were Salidroside-targeted,including 20 ferroptosis genes.DDIT3,GSK3B,HIF1A,MAPK1,MTOR(FRAP),PARP1,PIK3CA,RELA(NFKB3),SIRT1,VEGFA,PRKAA1,MAPK3,and PRKAA2 gene mRNA expressions were aberrantly expressed in gastric cancer(P<0.05).The aberrant expression of DDIT3,MAPK3,VEGFA,PRKAA2,RELA(NFKB3),HIF1A,MAPK1,PIK3CA,SIRT1,PRKAA1,PARP1 mRNA were correlated with the prognosis of gastric cancer patients(P<0.05).GO analysis was mainly enriched in the regulation of cell division,proliferation and apoptosis,while KEGG analysis was mainly enriched in the regulation of PI3K-Akt,HIF-1,FoxO signaling pathways,apoptosis,autophagy,Kaposi's sarcoma-associated herpesvirus infection,reactive oxygen species chemical carcino genesis,cancer pathway,PD-L1 expression in tumors and PD-1 checkpoint pathway and longevity regulation pathway.According to the molecular docking dat
作者
余水红
夏静
查洁
刘慧娟
YU Shuihong;XIA Jing;ZHA Jie;LIU Huijuan(Department of Pathogeny and Biochemistry,School of Basic Medicine,Anqing Medical College,Anhui 246052;Department of Pharmacy,Anqing Hospital of Traditional Chinese Medicine)
出处
《南通大学学报（医学版）》
2024年第4期313-319,共7页
Journal of Nantong University(Medical sciences)
基金
安徽省高校自然科学基金重点项目(2022AH052549,2023AH053426)
关键词
红景天苷
胃癌
铁死亡
作用机制
Salidroside
gastric cancer
ferroptosis
mechanism
