Identification Of Differentially Expressed Genes MiRNAs And Signaling Pathways In Docetaxel-resistant Prostate Cancer By Integrated Bioinformatics Analysis

ObjectsProstate cancer(PCa)is one of the deadly malignant tumors.About one-fifth of the total number of new male cancers in the United States in 2018 is prostate cancer,with a total of about 164,649 new cases and 29,430 deaths.Chemotherapy with docetaxel(a taxane member)is used as a first-line standard chemotherapy for patients with metastatic castration-resistant prostate cancer(m CRPC)and has been identified as prolonged in patients with metastatic castration-resistant prostate cancer(m CRPC)Survival period.However,due to the development of drug resistance,a significant proportion of m CRPC patients treated with docetaxel eventually became refractory and progressed.It has been recognized that many factors,including the tumor microenvironment,autophagy,etc.,are involved.Therefore,there is an urgent need to find potential causes of resistance to docetaxel chemotherapy.Here we apply comprehensive bioinformatics to identify key pathogenic genes,mi RNAs involved in docetaxel-resistant prostate cancer and reveal potential molecular mechanisms.MethodThe expression profiles of GSE33455,GSE64012 and GSE64013 from the Gene Expression Omnibus(GEO)database were downloaded,including 40 samples,13 prostate cancer samples and 27 docetaxel-resistant prostate cancer samples.GSE33455 and GSE64012 were analyzed to obtain differentially expressed genes(DEG),GSE64013 to obtain differentially expressed mi RNAs(DER),in-depth analysis by bioinformatics methods.GO(Gene Ontology)analysis and KEGG(Kyoto Encyclopedia of Genes and Genomes)pathway analysis were performed by R package cluster Profiler and used to explain DEGs.The protein-protein interaction(PPI)network of DEG was constructed from the STRING database.A total of 141 DEGs were identified in the GEO dataset,and Cytohubba(software in Cytoscape)was used to obtain the top 15 core genes in the PPI network.The target mi RNA of the central gene was obtained by Fun Rich.Next,in order to screen the target mi RNAs of the hub gene,an online tool was used to map the target mi RNAs of the core gene and the Venn diagram of the DERs.Finally,the online analysis website UALCAN(http://ualcan.path.uab.edu/index.html)was used to analyze the inter-group content and determine the hub genes,mi RNAs and signaling pathways of docetaxel-resistant prostate cancer.Results1.GEO2 R was used to screen the GSE33455_DU-145 dataset(P value <0.05,log FC> = 1 or <=-1),2338 differential genes were obtained.Among them,1188down-regulated genes and 1150 up-regulated genes were identified.2941 differential genes were screened from the GSE33455_PC3 dataset,including 1203 up-regulated genes and 1738 down-regulated genes.In addition,2785 DEGs were screened from the GSE64012 dataset,including 785 up-regulated genes and 2000 down-regulated genes.Finally,833 DERs were screened from the GSE64013 dataset,including 519up-regulated mi RNAs and 314 down-regulated mi RNAs.2.Through RRA integration bioinformatics analysis,we identified 141,of which43 were up-regulated and 98 down-regulated.And carry out GO analysis and KEGG pathway enrichment analysis.3.The DEG expression product in docetaxel-resistant prostate cancer was constructed using the STRING database(http://string-db.org)to construct a PPI network,and the connection in the PPI network was obtained using Cytohubba(software in Cytoscape).The top 15 core genes are CDH1,CCL2,IL8,TLR4,PTGS2,MX1,IFIH1,ISG15,IFIT1,MMP7,PLAU,KDR,GJA1,CLDN7,RUNX2.4.Using Fun Rich to predict the targeted mi RNAs of 15 core genes,the predicted core gene targeting mi RNAs and DERs were combined to obtain a mi RNA:hsa-mi R-193a-3p.5.The genes that were differentially expressed by TCGA and analyzed for P<0.05 were TLR4,KDR,PTGS2,IFIH1,ISG15,PLAU,GJA1,and CLDN7.The differentially expressed genes with similar expression and the lack of enrichment to the corresponding signaling pathways were removed,and the key genes PLAU,PTG3 and hsa-mi R-193a-3p were obtained,and the signaling pathway hsa04064(NF-kappa B signaling)was obtained.ConclusionA total of 141 DEGs were identified in the GEO dataset,of which 43 genes were up-regulated and 98 genes were down-regulated.Comprehensive bioinformatics is used to identify key pathogenic genes involved in docetaxel-resistant prostate cancer.This experiment finally obtained the potential inducement of docetaxel resistance in prostate cancer because high expression of hsa-mi R-193a-3p and then act on PLAU,which inhibited the expression of PLAU,thereby affecting the hsa04064(NF-kappa B signaling)pathway,causing the prostate Docetaxel resistance in cancer cells,and low expression of PTGS may synergistically achieve docetaxel resistance through DKK3 and TGF-β signaling pathways.