Abstract
There is increasing evidence that circular RNA (circRNA) are involved in cancer development, but the regulation and function of human circRNA remain largely unknown. In this study, we demonstrated that ZKSCAN1, a zinc finger family gene, is expressed in both linear and circular (circZKSCAN1) 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 circZKSCAN1 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 cirZKSCAN1 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 circZKSCAN1 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 circZKSCAN1 mediated several cancer‐related signaling pathways, suggesting a nonredundant role for ZKSCAN1 mRNA and circRNA. In conclusion, our results revealed two post‐translational products (ZKSCAN1 mRNA and circZKSCAN1) that cooperated closely with one another to inhibit growth, migration, and invasion of HCC. cirZKSCAN1 might be a useful marker for the diagnosis of HCC.
Highlights
IntroductionStatistics have shown that approximately 740 000 people are newly diagnosed with Hepatocellular carcinoma (HCC) and that this disease accounts for approximately 700 000 deaths annually worldwide (Marquardt et al, 2015)
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide
Most of the ZKSCAN1 protein was located in the cytoplasm, and more often in mitochondria in the normal liver tissues
Summary
Statistics have shown that approximately 740 000 people are newly diagnosed with HCC and that this disease accounts for approximately 700 000 deaths annually worldwide (Marquardt et al, 2015). 55% of newly diagnosed patients were found in China, which was regarded as the area with the highest prevalence of HCC (Torre et al, 2015). With the improvement of diagnostic approaches and treatment strategies, patients with HCC can be detected at an early stage and subjected to radical surgeries with a favorable prognosis. As a biomarker, AFP has limited clinical diagnostic value (especially for early diagnosis). To improve the therapeutic effect and prognosis of patients with HCC, it is imperative to search for more efficient biomarkers to increase the rate of early diagnosis of HCC. A better understanding of the potential molecular mechanism underlying the occurrence and development of liver cancer, searches for new diagnostic markers and new targets of clinical treatment are of great important in liver cancer research
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