Abstract
Circular RNAs (circRNAs), one kind of noncoding RNAs, can interact with miRNA and transcription factors to regulate gene expression. However, little is known on which circRNA is crucial for the pathogenesis of hepatocellular carcinoma (HCC). CircRNA expression profile was analyzed by a microarray. Regulatory gene targets were predicted by bioinformatics analysis and validated by luciferase assay. Their expression was determined by qRT-PCR and Western blotting. DNA methylation was determined by methylation-specific PCR. Gene knockdown and overexpression were mediated by lentivirus-mediated shRNA and transfection with plasmids for cDNA expression, respectively. MTT assay, wound-healing assay, transwell invasion assay, and flow cytometry were used to determine malignant behaviors of HCC cells. HCC xenograft mouse model was used to determine the in vivo effects of circRNA-5692. CircRNA-5692 expression was downregulated in HCC tissues, and circRNA-5692 overexpression attenuated the malignant behaviors of HCC cells. Bioinformatics predicted that circRNA-5692 interacted with miR-328-5p, which targeted the DAB2IP mRNA. Actually, miR-328-5p promoted the malignant behaviors of HCC cells, while DAB2IP had opposite effects. Moreover, circRNA-5692 overexpression inhibited the growth of xenograft HCC tumors in vivo by decreasing miR-328-5p expression to enhance DAB2IP expression. In conclusion, the circRNA-5692–miR-328-5p–DAB2IP regulatory pathway inhibits the progression of HCC. Our findings may provide potential new targets for the diagnosis and therapy of HCC.
Highlights
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver carcinomas in the world[1,2]
It was notable that the circRNA-5692 was encoded by the GLIS2 gene and most significantly downregulated in five hepatocellular carcinoma (HCC) tissues and HCC cells (Fig. 1b, c)
Stratification analyses indicated that the lower circRNA-5692 expression was significantly associated with abnormal higher levels of AFP (P = 0.001), cirrhosis history (P = 0.001), larger tumor size (P = 0.042), and distant metastasis (P = 0.025), but not other measures tested in this population
Summary
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver carcinomas in the world[1,2]. HCC is one of the leading causes of malignancy in humans, and has high morbidity and mortality rates[3]. Despite of significant advance in therapeutic strategies for HCC, the 5-year survival rate of HCC patients remains low[4]. Little is known on the molecular pathogenesis and therapeutic targets of HCC. CircRNAs are covalently closed continuous loop type of single-stranded RNAs in mammalian cells ubiquitously and regulate gene expression[6]. Previous studies have shown that circRNAs can regulate malignant behaviors, including the proliferation, migration, invasion, and apoptosis of cancer cells[7,8,9,10]. CircRNA hsa_circ_0000096 regulates the proliferation and migration of gastric cancer cells by modulating the gene expression of cyclin D1, cyclin-dependent kinase-6
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