Abstract
Hepatocellular carcinoma (HCC) is a more common malignancy than the majority of cancers and ranks second in the world’s top causes of cancer-related mortality. The objective of the study was to investigate and explain how circularRNA-9119 (circ9119) regulated the properties of HCC cell lines. Cancer cells isolated from HCC patients and HCC cell lines showed clearly upregulated expression of circ9119 and Janus kinase 1 (JAK1) with decreased levels of miR-26a compared to healthy controls and normal hepatic cells. To determine the function of circ9119, circ9119 was silenced in HCC cells, resulting in significantly less proliferation of HCC cells and increasing apoptosis. Circ9119 silencing also resulted in the upregulation of miR-26a. Bioinformatics prediction and dual-luciferase reporter assays showed that circ9119 targeted miR-26a. Further studies revealed that miR-26a had the opposite effect on circ9119; the inhibition of miR-26a antagonized circ9119 silencing, leading to reduced cell proliferation and increased apoptosis, while the ectopic overexpression of miR-26a impaired cell growth. Additionally, we found that the JAK1 3′-UTR was targeted by miR-26a; a decrease in the levels of JAK1 protein and mRNA followed transfection of a miR-26a mimic. Administration of the JAK1 inhibitor, baricitinib, caused the activation of signal transducer and activator of transcription 3 (STAT3) and revealed an effect similar to that of circ9119 silencing on cell proliferation and apoptosis. These results showed that circ9119 could modulate apoptosis, and broadly, cell proliferation by competitively binding miR-26a, which targeted JAK1-STAT3, in HCC cell lines. This study is a novel description of circ9119 regulation of HCC.
Highlights
Among populations diagnosed and living with cancer, those with primary liver cancer form one of the largest populations and contribute to most cancer deaths
Circ9119 was upregulated in human HepG2, BEL-7404, SMMC-7721, and Huh-7 (HCC cell lines), compared with normal healthy hepatic cells (HHCs) (Fig. 1b), suggesting that circ9119 is involved in hepatocellular carcinoma (HCC) development
We found that nuclear translocation of signal transducer and activator of transcription 3 (STAT3) was reduced upon incubation with baricitinib (Fig. 7c, d), indicating that the Janus kinase 1 (JAK1)-STAT3 signal axis was blocked by baricitinib
Summary
Among populations diagnosed and living with cancer, those with primary liver cancer form one of the largest populations and contribute to most cancer deaths. Hepatocellular carcinoma (HCC) is a highly invasive subtype of primary liver cancer with metastatic potential and a low survival rate. It forms 75–85% of all primary liver cancers[1]. Circular RNAs (circRNAs) are a type of non-coding RNA (ncRNA) that feature microRNA (miRNA) response elements that can bind to messenger RNAs (mRNAs), facilitating recent evidence of their potential to regulate genes[3]. As molecular sponges of miRNAs, circRNAs derepress miRNA target genes, affecting post-transcriptional regulation[4]. Primary factors contributing to the low survival among HCC patients include the absence of working biomarkers and the presence of classical biomarkers, such as des-gamma-carboxyprothrombin (DCP), alpha-fetoprotein-
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