基于GEO数据库的多靶点酪氨酸激酶抑制剂索拉非尼致心肌毒性生物标志物的筛选  

Screening of biomarkers for cardiotoxicity induced by the multi-target tyrosine kinase inhibitor sorafenib based on the GEO database

作　　者：吴洁 赵光斌 马虹[1] WU Jie;ZHAO Guang-bin;MA Hong(Department of General Medicine,Chengdu Sixth People's Hospital,Chengdu 610051,Sichuan,CHINA;Shuangshui Nian Community Health Service Center of Longhua District of Chengdu,Chengdu 610051,Sichuan,CHINA)

机构地区：[1]成都市第六人民医院全科医学科,四川成都610051 [2]成都市成华区双水碾社区卫生服务中心,四川成都610051

出　　处：《海南医学》2024年第16期2281-2287,共7页Hainan Medical Journal

基　　金：四川省转移支付项目(编号:2017SZYZF0002)。

摘　　要：目的探索多靶点激酶抑制剂索拉非尼对心肌细胞损伤的关键基因,为临床防治索拉非尼对心肌细胞损伤提供新靶点。方法GEO数据库中下载数据集GSE88944,该数据集总例数为10例,其中正常组5例,索拉非尼组5例;采用GEO2R在线工具进行数据分析,以logFC(fold change)绝对值>2且Padj<0.05为标准筛选差异基因。对差异表达编码基因分别进行GO富集及KEGG通路分析,构建蛋白-蛋白互作网络,筛选关键基因,构建关键基因及编码蛋白-蛋白互作网络。结果共筛选出差异基因238个,其中蛋白编码差异基因(Pc-DEGs)208个,非编码差异基因30个,Pc-DEGs中上调基因56个、下调基因152个;Pc-DEGs主要参与的生物学过程包括血管生成、心肌收缩、血压的调节、血管生成的正向调节;细胞组分细胞外区域、质膜的整体组成部分、Z盘;分子功能主要有受体结合、肝素结合、整合素结合、钙离子结合等。KEGG结果显示,Pc-DEGs主要富集在肥厚型心肌病、MAPK信号传导途径、扩张型心肌病、cAMP信号传导途径、心肌收缩等信号通路;共筛选出CTGF(CCN2)、FOS、JUN、POSTN、EDN1、SERPINE1、IGF1等7个关键下调基因。结论CTGF(CCN2)、FOS、JUN、POSTN、EDN1、SERPINE1、IGF1是首个口服多靶点酪氨酸激酶抑制剂索拉非尼致心肌毒性的关键下调基因,这可能为多靶点酪氨酸激酶抑制剂索拉菲尼心肌毒性提供新的治疗靶点。Objective To explore the key genes of myocardial cell injury by sorafenib,a multi-target kinase inhibitor,and to provide new targets for clinical prevention and treatment of myocardial cell injury by sorafenib.Methods The data set GSE88944 was downloaded from the GEO database,which consisted of 10 cases in total,including 5 cases in the normal group and 5 cases in the sorafenib group.The data were analyzed using the GEO2R online tool,and differential genes were screened using the criteria of absolute value of logFC(fold change)>2 and Padj<0.05.The differentially expressed coding genes were analyzed by GO enrichment and KEGG pathway,and the protein-protein interaction network was constructed.The key genes were screened out,and the protein-protein interaction network of the key genes-coded proteins was constructed.Results A total of 238 differentially expressed genes were screened,including 208 protein-coding differentially expressed genes(Pc-DEGs)and 30 non-coding differentially expressed genes.In the Pc-DEGs,56 up-regulated genes and 152 down-regulated genes were found.The biological processes in which the Pc-DEGs were mainly involved included angiogenesis,myocardial contraction,the regulation of blood pressure,and positive angiogenesis;cellular components involved the extracellular region,the integral component of plasma membrane,and Z disk;molecular functions mainly included receptor binding,heparin binding,integrin binding,calcium binding,etc.KEGG results showed that Pc-DEGs were mainly enriched in signaling pathways such as hypertrophic cardiomyopathy,MAPK signaling pathway,dilated cardiomyopathy,cAMP signaling pathway,and myocardial contraction.A total of 7 key down-regulated genes were selected through screening:CTGF(CCN2),FOS,JUN,POSTN,EDN1,SERPINE1,and IGF1.Conclusion CTGF(CCN2),FOS,JUN,POSTN,EDN1,SERPINE1,and IGF1 are the first key down-regulated genes for cardiotoxicity caused by oral multi-target tyrosine kinase inhibitor sorafenib,which may provide new therapeutic targets for cardiotoxicity of multi-t

关 键 词：酪氨酸激酶抑制剂 索拉非尼 心肌细胞 生物标志物 

分 类 号：R318.11[医药卫生—生物医学工程]