Abstract
As a recently discovered noncoding RNA, circular RNAs (circRNAs) have been identified to play key roles in cancer biology; however, the detailed functions and mechanisms of circRNAs in hepatocellular carcinoma (HCC) remain largely unclarified. RNA-seq analysis was used to screen the expression profiles of circRNAs in HCC. CircZNF566 expression in HCC tissues and cell lines was detected by qRT-PCR. In vitro CCK-8, colony formation, wound healing, transwell migration, and invasion assays and in vivo tumorigenesis and metastasis assays were conducted to determine the functions of circZNF566. Luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays were also performed to confirm the relationship between circZNF566 and miR-4738-3p. Bioinformatics analysis and luciferase reporter assays were employed to determine whether miR-4738-3p regulates tryptophan 2,3-dioxygenase (TDO2) expression. Finally, immunohistochemistry (IHC) was used to detect the level of TDO2 and determine its prognostic value. CircZNF566 was significantly upregulated in HCC tissues and cell lines. High circZNF566 expression in HCC tissues was positively correlated with clinicopathological features and poor prognosis. Functionally, in vitro experiments showed that circZNF566 promoted HCC cell migration, invasion, and proliferation, whereas in vivo experiments showed that circZNF566 promoted tumorigenesis and metastasis. Mechanistically, circZNF566 acted as a miR-4738-3p sponge to relieve the repressive effect of miR-4738-3p on its target TDO2. In addition, miR-4738-3p suppressed HCC cell migration, invasion, and proliferation, while TDO2 was positively correlated with pathological features and poor prognosis and promoted cell migration, invasion, and proliferation in HCC. CircZNF566 is a novel tumor promoter in HCC and functions through the circZNF566/ miR-4738-3p /TDO2 axis; in addition, circZNF566 may serve as a novel diagnostic marker, prognostic indicator, and target for the treatment of HCC.
Highlights
According to cancer statistics, liver cancer is one of the most fatal cancers and the mortality of liver cancer has rapidly increased[1]
CircZNF566 expression was detected by quantitative real-time PCR (qRT-PCR) in 57 pairs of fresh frozen Hepatocellular carcinoma (HCC) tissues and matched normal liver tissues and we found that circZNF566 expression was higher in the HCC tissues (78.95%, 45/57) (Fig. 1g, Supplementary Fig. S1b)
RNA-seq analysis of five matched pairs of HCC tissues and normal tissues was performed to characterize the expression of circRNA transcripts (Fig. 1a)
Summary
Liver cancer is one of the most fatal cancers and the mortality of liver cancer has rapidly increased[1]. Natural endogenous circRNAs are inherently resistant to exonucleolytic RNA decay and contain selectively conserved microRNA (miRNA) target sites, so circRNAs can either act as “miRNA sponges” and competitively bind miRNAs to regulate posttranscriptional activity or interact with RNA polymerase II in the nucleus to regulate transcription[9,11,13]. These findings suggest that circRNAs might be a potential biomarker and therapeutic target for cancer
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