Article: The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2

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TitleThe putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2
AuthorsZheng, F2
Liao, YJ2
Cai, MY2
Liu, YH1
Liu, TH2
Chen, SP2
Bian, XW3
Guan, XY2
Lin, MC4
Zeng, YX2
Kung, HF2 4
Xie, D2
Issue Date2012
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
CitationGut, 2012, v. 61 n. 2, p. 278-289 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gut.2011.239145
AbstractBACKGROUND: 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.
ISSN0017-5749
2011 Impact Factor: 10.111
2011 SCImago Journal Rankings: 0.883
DOIhttp://dx.doi.org/10.1136/gut.2011.239145
ISI Accession Number IDWOS:000298665000017
Funding AgencyGrant Number
973 project of China2010CB529400
2010CB912802
863 project of China2007AA021901
Guangzhou Science and Technology Bureau Foundation2005Z1-E0131
Funding Information:

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).

ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorZheng, F
dc.contributor.authorLiao, YJ
dc.contributor.authorCai, MY
dc.contributor.authorLiu, YH
dc.contributor.authorLiu, TH
dc.contributor.authorChen, SP
dc.contributor.authorBian, XW
dc.contributor.authorGuan, XY
dc.contributor.authorLin, MC
dc.contributor.authorZeng, YX
dc.contributor.authorKung, HF
dc.contributor.authorXie, D
dc.date.accessioned2012-06-26T06:12:09Z
dc.date.available2012-06-26T06:12:09Z
dc.date.issued2012
dc.description.abstractBACKGROUND: 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.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationGut, 2012, v. 61 n. 2, p. 278-289 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gut.2011.239145
dc.identifier.doihttp://dx.doi.org/10.1136/gut.2011.239145
dc.identifier.epage289
dc.identifier.hkuros203476
dc.identifier.isiWOS:000298665000017
Funding AgencyGrant Number
973 project of China2010CB529400
2010CB912802
863 project of China2007AA021901
Guangzhou Science and Technology Bureau Foundation2005Z1-E0131
Funding Information:

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).

dc.identifier.issn0017-5749
2011 Impact Factor: 10.111
2011 SCImago Journal Rankings: 0.883
dc.identifier.issue2
dc.identifier.pmid21672940
dc.identifier.scopuseid_2-s2.0-84855191863
dc.identifier.spage278
dc.identifier.urihttp://hdl.handle.net/10722/150845
dc.identifier.volume61
dc.languageeng
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
dc.publisher.placeUnited Kingdom
dc.relation.ispartofGut
dc.relation.referencesReferences in Scopus
dc.rightsGut. Copyright © BMJ Publishing Group.
dc.rightsThis article has been accepted for publication in [Gut]. The definitive copyedited, typeset version [Gut, 2012, v. 61 n. 2, p. 278-289] is available online at: www.gut.bmj.com
dc.subject.meshCarcinoma, Hepatocellular - metabolism - pathology
dc.subject.meshDNA-Binding Proteins - metabolism
dc.subject.meshLiver Neoplasms - metabolism - pathology
dc.subject.meshMicroRNAs - metabolism
dc.subject.meshTranscription Factors - metabolism
dc.titleThe putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2
dc.typeArticle
Author Affiliations
  1. Guangdong Provincial People's Hospital
  2. Sun Yat-Sen University
  3. Third Military Medical University
  4. Chinese University of Hong Kong