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The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2
  1. Fang Zheng1,2,
  2. Yi-Ji Liao1,2,
  3. Mu-Yan Cai1,3,
  4. Yan-Hui Liu4,
  5. Tian-Hao Liu1,2,5,
  6. Shu-Peng Chen1,2,
  7. Xiu-Wu Bian6,
  8. Xin-Yuan Guan1,2,
  9. Marie C Lin7,
  10. Yi-Xin Zeng1,2,
  11. Hsiang-Fu Kung1,7,
  12. Dan Xie1,2
  1. 1The State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
  2. 2Department of Experimental Research, Sun Yat-Sen University, Guangzhou, China
  3. 3Department of pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
  4. 4Department of Pathology, Guangdong Provincial People's Hospital, Guangzhou, China
  5. 5Department of oncology, Sun-Yet-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
  6. 6Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
  7. 7The State Key Laboratory of Oncology in South China, the Chinese University of Hong Kong, Hong Kong, China
  1. Correspondence to Dr Dan Xie, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No. 651, Dongfeng Road East, 510060 Guangzhou, China; xied{at}mail.sysu.edu.cn

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.

  • Hepatocellular carcinoma
  • microRNA-124
  • metastasis
  • epithelial-mesenchymal transition
  • cancer genetics
  • cell biology

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Footnotes

  • Funding This study was supported by grants made under the 973 project of China (Nos 2010CB529400 and 2010CB912802) and the 863 project of China (No 2007AA021901), and by a grant from the Guangzhou Science and Technology Bureau Foundation (No 2005Z1-E0131).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the institute research ethics committee of the Cancer Center, Sun Yat-Sen University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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