Three novel circRNAs upregulated in tissue and plasma from hepatocellular carcinoma patients and their regulatory network.

ABSTRACT

BACKGROUND: The regulatory roles of circular RNAs (circRNAs) in tumorigenesis have attracted increasing attention. However, novel circRNAs with the potential to be used as serum/plasma biomarkers and their regulatory mechanism in the pathogenesis of hepatocellular carcinoma (HCC) remain explored. METHODS: CircRNA expression profiles of tumor tissues and plasma samples from HCC patients were compiled and jointly analyzed. CircRNA-miRNA-mRNA interactions were predicted by bioinformatics tools. The expression of interacting miRNAs and mRNA was verified in independent datasets. Survival analysis and pathway enrichment analysis were conducted on hub genes. RESULTS: We identified three significantly up-regulated circRNAs (hsa_circ_0009910, hsa_circ_0049783, and hsa_circ_0089172) both in HCC tissues and plasma samples. Two of them were validated to be indeed circular and could be excreted from hepatoma cells. We further revealed four miRNAs (hsa-miR-455-5p, hsa-miR-615-3p, hsa-miR-18a-3p, hsa-miR-4524a-3p) that targeting circRNAs and expressed in human HCC samples, and 95 mRNAs targeted by miRNAs and significantly up-regulated in two HCC cohorts. A protein-protein interaction network revealed 19 hub genes, 12 of them (MCM6, CCNB1, CDC20, NDC80, ZWINT, ASPM, CENPU, MCM3, MCM5, ECT2, CDC7, and DLGAP5) were associated with reduced survival in two HCC cohorts. KEGG, Reactome, and Wikipathway enrichment analysis indicated that the hub genes mainly functioned in DNA replication and cell cycle. CONCLUSIONS: Our study uncovers three novel deregulated circRNAs in tumor and plasma from HCC patients and provides an insight into the pathogenesis from the circRNA-miRNA-mRNA regulatory network.