The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Issue 2 (14th June 2011)

• Record Type: Journal Article
• Authors: Zheng, Fang; Liao, Yi-Ji; Cai, Mu-Yan; Liu, Yan-Hui; Liu, Tian-Hao; Chen, Shu-Peng; Bian, Xiu-Wu; Guan, Xin-Yuan; Lin, Marie C; Zeng, Yi-Xin; Kung, Hsiang-Fu; Xie, Dan
• Is Part Of: Gut. Volume 61:Issue 2(2012)
• Page Start: 278
• Page End: 289
• Publication Date: 2011-06-14
• Subjects: Hepatocellular carcinoma -- microRNA-124 -- metastasis -- epithelial-mesenchymal transition -- cancer genetics -- cell biology; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2011.239145
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-124) in hepatocellular carcinoma (HCC). Objective: To determine the status of miR-124 expression and its underlying mechanisms in the pathogenesis of HCC. Methods: The expression levels of miR-124 were first examined in HCC cell lines and tumour tissues by real-time PCR. The in vitro and in vivo functional effect of miR-124 was examined further. A luciferase reporter assay was conducted to confirm target associations. Results: The expression levels of miR-124 were frequently reduced in HCC cells and tissues, and low-level expression of miR-124 was significantly associated with a more aggressive and/or poor prognostic phenotype of patients with HCC (p<0.05). In HCC cell lines, stable overexpression of miR-124 was sufficient to inhibit cell motility and invasion in vitro, and suppress intrahepatic and pulmonary metastasis in vivo. In addition, ectopic overexpression of miR-124 in HCC cells inhibited epithelial–mesenchymal cell transition, formation of stress fibres, filopodia and lamellipodia. Further studies showed that miR-124 could directly target the 3 ′ -untranslated region (3′-UTR) of both ROCK2 and EZH2 mRNAs, and suppress their mRNA and protein expressions. These findings suggest that miR-124 plays a critical role in regulating cytoskeletal events and epithelial–mesenchymal cell transition and, ultimately, inhibits the invasive and/or metastatic potential of HCC, probably by its direct target on ROCK2 and EZH2 genes. These results provide functional and mechanistic links between the tumour suppressor miRNA-124 and the two oncogenes ROCK2 and EZH2 on the aggressive nature of HCC. Conclusion: These data highlight an important role for miR-124 in the regulation of invasion and metastasis in the molecular aetiology of HCC, and suggest a potential application of miR-124 in prognosis prediction and cancer treatment.