ZKSCAN1 gene and its related circular RNA (circ ZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways.

There is increasing evidence that circular RNA (circ RNA) are involved in cancer development, but the regulation and function of human circ RNA remain largely unknown. In this study, we demonstrated that ZKSCAN1, a zinc finger family gene, is expressed in both linear and circular ( circ ZKSCAN1) forms of RNA in human hepatocellular carcinoma ( HCC) tissues and cell lines. Here, we analyzed a cohort of 102 patients and found that expression of both ZKSCAN1 mRNA and circ ZKSCAN1 was significantly lower ( P < 0.05) in the HCC samples compared with that in matched adjacent nontumorous tissues by reverse transcription PCR ( RT- PCR). The low expression level of ZKSCAN1 was only associated with tumor size ( P = 0.032), while the cir ZKSCAN1 levels varied in patients with different tumor numbers ( P < 0.01), cirrhosis ( P = 0.031), vascular invasion ( P = 0.002), or microscopic vascular invasion ( P = 0.002), as well as with the tumor grade ( P < 0.001). Silencing both ZKSCAN1 mRNA and circ ZKSCAN1 promoted cell proliferation, migration, and invasion. In contrast, overexpression of both forms of RNA repressed HCC progression in vivo and in vitro. Silencing or overexpression of both forms of RNA did not interfere with each other. RNA-seq revealed a very different molecular basis for the observed effects; ZKSCAN1 mRNA mainly regulated cellular metabolism, while circ ZKSCAN1 mediated several cancer-related signaling pathways, suggesting a nonredundant role for ZKSCAN1 mRNA and circ RNA. In conclusion, our results revealed two post-translational products ( ZKSCAN1 mRNA and circ ZKSCAN1) that cooperated closely with one another to inhibit growth, migration, and invasion of HCC. cir ZKSCAN1 might be a useful marker for the diagnosis of HCC. [ABSTRACT FROM AUTHOR]