Abstract
Clear cell renal cell carcinoma (ccRCC) is the most representative subtype of renal cancer. CircRNA acts as a kind of ceRNA to play a role in regulating microRNA (miRNA) in many cancers. However, the potential pathogenesis role of the regulatory network among circRNA/miRNA/mRNA is not clear and has not been fully explored. CircRNA expression profile data were obtained from GEO datasets, and the differentially expressed circRNAs (DECs) were identified through utilizing R package (Limma) firstly. Secondly, miRNAs that were regulated by these circRNAs were predicted by using Cancer-specific circRNA database and Circular RNA Interactome. Thirdly, some related genes were identified by intersecting targeted genes, which was predicted by a web tool (miRWalk) and differentially expressed genes, which was obtained from TCGA datasets. Function enrichment was analyzed, and a PPI network was constructed by Cytoscape software and DAVID web set. Subsequently, ten hub-genes were screened from the network, and the overall survival time in patients of ccRCC with abnormal expression of these hub-genes were completed by GEPIA web set. In the last, a circRNA/miRNA/mRNA regulatory network was constructed, and potential compounds and drug which may have the function of anti ccRCC were forecasted by taking advantage of CMap and PharmGKB datasets. Six DECs (hsa_circ_0029340, hsa_circ_0039238, hsa_circ_0031594, hsa_circ_0084927, hsa_circ_0035442, hsa_circ_0025135) were obtained and six miRNAs (miR-1205, miR-657, miR-587, miR-637, miR-1278, miR-548p) which are regulated by three circRNAs (hsa_circ_0084927, hsa_circ_0035442, hsa_circ_0025135) were also predicted. Then 497 overlapped genes regulated by these six miRNAs above had been predicted, and function enrichment analysis revealed these genes are mainly linked with some regulation functions of cancers. Ten hub-genes (PTGER3, ADCY2, APLN, CXCL5, GRM4, MCHR1, NPY5R, CXCR4, ACKR3, MTNR1B) have been screened from a PPI network. PTGER3, ADCY2, CXCL5, GRM4 and APLN were identified to have a significant effect on the overall survival time of patients with ccRCC. Furthermore, one compound (josamycin) and four kinds of drugs (capecitabine, hmg-coa reductase inhibitors, ace Inhibitors and bevacizumab) were confirmed as potential therapeutic options for ccRCC by CMap analysis and pharmacogenomics analysis. This study implies the potential pathogenesis of the regulatory network among circRNA/miRNA/mRNA and provides some potential therapeutic options for ccRCC.
Highlights
Renal cancer is common cancer, and the incidence rates in males and females are 5% and 3%, respectively[1]
CircRNAs’ function can generalize as below (1) miRNA can regulate the post-transcriptional expression of target genes, and circRNA can act as a competing endogenous RNA to bind to miRNA like a sponge to regulate the function of miRNA, indirectly regulating the expression of genes (2) It can affect gene expression through interacting with RNA binding protein and modulating the stability of mRNAs (3) It can function as protein scaffolds and encode functional proteins in some cancer cells lines[6,7,8,9]
The process digraph is showed in Fig. 1: Firstly, circRNAs related microarray datasets of Clear cell renal cell carcinoma (ccRCC) were obtained from GEO database, and differential expressed circRNAs (DECs) were acquired
Summary
Renal cancer is common cancer, and the incidence rates in males and females are 5% and 3%, respectively[1]. Compared with linear RNA structure, circRNA has no 5′–3′ polarity and no polyA tail, making it a closed circular structure. It is more stable than linear RNA, and it is not degraded by RNA exonuclease or R Nase[5]. Some novel circRNAs may act as ceRNA to regulate gene expression in ccRCC, and their potential mechanisms have been investigated by utilizing gene chip and bioinformatics methods. To demonstrate whether the DECs function as ceRNAs in ccRCC, their related miRNAs and miRNA target genes have been collected, and a circRNA/miRNA/ mRNA network has been constructed. Pharmacogenomics analysis were conducted to predict bio-active compounds and potential drugs for the treatment of ccRCC, which may provide a new method in the latent therapeutic capacity of circRNAs in ccRCC
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