A circRNA–miRNA–mRNA network identification for exploring underlying pathogenesis and therapy strategy of hepatocellular carcinoma

Abstract

BackgroundCircular RNAs (circRNAs) have received increasing attention in human tumor research. However, there are still a large number of unknown circRNAs that need to be deciphered. The aim of this study is to unearth novel circRNAs as well as their action mechanisms in hepatocellular carcinoma (HCC).MethodsA combinative strategy of big data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology was employed to dig HCC-related circRNAs and to explore their potential action mechanisms. A connectivity map (CMap) analysis was conducted to identify potential therapeutic agents for HCC.ResultsSix differently expressed circRNAs were obtained from three Gene Expression Omnibus microarray datasets (GSE78520, GSE94508 and GSE97332) using the RobustRankAggreg method. Following the RT-qPCR corroboration, three circRNAs (hsa_circRNA_102166, hsa_circRNA_100291 and hsa_circRNA_104515) were selected for further analysis. miRNA response elements of the three circRNAs were predicted. Five circRNA–miRNA interactions including two circRNAs (hsa_circRNA_104515 and hsa_circRNA_100291) and five miRNAs (hsa-miR-1303, hsa-miR-142-5p, hsa-miR-877-5p, hsa-miR-583 and hsa-miR-1276) were identified. Then, 1424 target genes of the above five miRNAs and 3278 differently expressed genes (DEGs) on HCC were collected. By intersecting the miRNA target genes and the DEGs, we acquired 172 overlapped genes. A protein–protein interaction network based on the 172 genes was established, with seven hubgenes (JUN, MYCN, AR, ESR1, FOXO1, IGF1 and CD34) determined from the network. The Gene Oncology, Kyoto Encyclopedia of Genes and Genomes and Reactome enrichment analyses revealed that the seven hubgenes were linked with some cancer-related biological functions and pathways. Additionally, three bioactive chemicals (decitabine, BW-B70C and gefitinib) based on the seven hubgenes were identified as therapeutic options for HCC by the CMap analysis.ConclusionsOur study provides a novel insight into the pathogenesis and therapy of HCC from the circRNA–miRNA–mRNA network view.

RNA-seq reveals the circular RNA and miRNA expression profile of peripheral blood mononuclear cells in patients with rheumatoid arthritis

“…There are many previous studies showing that lncRNAs participate in the pathogenesis of RA and can be regarded as biomarkers for the diagnosis of RA [16,17]. Recently, there is increasing evidence proving that circRNAs are widely involved in various physiological and pathological processes, including the occurrence and development of many diseases, including lung cancer [18], liver cancer [19], gynecological diseases [20] and more. Little research about the role of circRNAs in RA has been conducted.…”

Circ‐IGF1R inhibits cell invasion and migration in non‐small cell lung cancer

“…CircRNA can act as an miRNA sponge to regulate its function and influence gene expression. Numerous studies have shown that the circRNA–miRNA–mRNA axis plays a key role in cancer‐associated pathways . By performing a binding site analysis of circ‐IGF1R–miRNA–VANGL2 and qRT‐PCR validation, we finally selected hsa‐miR‐1270.…”

“…Numerous studies have shown that the circRNA-miRNA-mRNA axis plays a key role in cancer-associated pathways. [34][35][36] By performing a binding site analysis of circ-IGF1R-miRNA-VANGL2 and qRT-PCR validation, we finally selected hsa-miR-1270. Previous studies have found that miR-1270 is upregulated in osteosarcoma, human renal cancer, and papillary thyroid cancer.…”

Circ_0080425 inhibits cell proliferation and fibrosis in diabetic nephropathy via sponging miR‐24‐3p and targeting fibroblast growth factor 11

“…Generally, circRNAs canonically function as microRNA (miRNA) sponges to competitively bind to its target genes, which led to dysregulated gene expression and altered signaling (Hansen et al, ). An emerging evidence has elucidated the important roles of “circRNA–miRNA–mRNA” axis in a variety of developmental pathways and diseases pathogenesis (Andres‐Leon, Nunez‐Torres, & Rojas, ; Rong et al, ; Xiong et al, ). Although several studies have implied the link between circRNAs and DN development (Gu et al, ; Hu et al, ), comprehensive investigations are required to unveil their functions and regulatory network.…”

“…Generally, circRNAs canonically function as microRNA (miRNA) sponges to competitively bind to its target genes, which led to dysregulated gene expression and altered signaling (Hansen et al, 2013). An emerging evidence has elucidated the important roles of "circRNA-miRNA-mRNA" axis in a variety of developmental pathways and diseases pathogenesis (Andres-Leon, Nunez-Torres, & Rojas, 2016;Rong et al, 2017;Xiong et al, 2018).…”