Abstract
BackgroundHCC is one of the most common malignancies with an increasing incidence worldwide, especially in Asian countries. However, even though targeted cancer therapy drugs such as sorafenib and regorafenib are available, the overall outcome of HCC remains unsatisfactory. Thus, it is urgent to investigate the molecular mechanisms of HCC progression, so as to provide accurate diagnostic criteria and therapeutic targets.MethodsRNA-seq data was used to identify and quantify circular RNAs (circRNAs). DESeq2 was used to identify the differentially expressed circRNAs. miRNA binding sites within circRNAs were identified by miRanda. Gene set enrichment analysis (GSEA) was conducted to predict the biological function of circRNAs.ResultsThe differential expression analysis identified 107 upregulated and 95 downregulated circRNAs in HCC tissues. We observed that a differentially expressed circRNA (DE-circRNA), hsa_circ_0141900 was highly negatively correlated with its parental gene RAB1A (PCC < -0.6), which was also closely associated with mTOR signaling pathway. Moreover, we also constructed competing endogenous RNA (ceRNA) network to identify key circRNAs involved in HCC. Notably, hsa_circ_0002130 and hsa_circ_0008774 were highly correlated with the genes involved in gluconeogenesis and HNF3A pathway via the target genes, GOT2 and AR, suggesting that the two circRNAs might regulate these pathways, respectively. Survival analysis revealed that GOT2 was associated with favorable prognosis. Furthermore, high expression of hsa_circ_0002130 was found to inhibit tumor cell growth and promotes GOT2 expression.ConclusionIn summary, the circRNAs highlighted by the integrative analysis greatly improved our understanding of the underlying mechanism of circRNAs in HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies with an increasing incidence worldwide [1, 2]
It is urgent to investigate the molecular mechanisms of HCC progression, so as to provide accurate diagnostic criteria and therapeutic targets
We observed that a differentially expressed circular RNAs (circRNA) (DE-circRNA), hsa_circ_0141900 was highly negatively correlated with its parental gene RAB1A (PCC < -0.6), which was closely associated with mTOR signaling pathway
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies with an increasing incidence worldwide [1, 2]. Previous study has identified 525 and 323 lncRNAs as recurrently downregulated or upregulated in HCC patients [1]. LncRNA-activated by TGF-b (lncRNA-ATB) has the ability to upregulate ZEB1 and ZEB2, and predispose HCC patients to metastases, while lncRNA downregulated in liver cancer stem cells (lnc-DILC) functions to suppress the expression of inflammatory cytokine IL−6, which in turns inhibits IL6-STAT3 autocrine signaling and suppress LCSC propagation [7, 8]. CircHIPK3 could sponge to 9 miRNAs, including miR124, miR-152, miR193a, miR-29a, miR-29b, miR-338, miR-379, miR-584 and miR654, and circRNA-ITCH was found to sponge to miR-7, miR-17, and miR-214 [9] While these circRNAs and their targets are greatly associated with tumorigenesis and progression, the underlying mechanism is yet not fully appreciated. It is urgent to investigate the molecular mechanisms of HCC progression, so as to provide accurate diagnostic criteria and therapeutic targets
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