File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice

TitlePPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice
Authors
Keywordsheparanase
hepatocellular carcinoma metastasis
matrix metallopeptidase
PPARg
tissue inhibitors of metalloproteinase
Issue Date2012
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
Citation
British Journal Of Cancer, 2012, v. 106 n. 9, p. 1486-1494 How to Cite?
AbstractBackground: We have previously demonstrated that peroxisome proliferator-activated receptor (PPARγ) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPARγ on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms. Methods: Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPARγ (Ad-PPARγ) or Ad-lacZ and treated with or without PPARγ agonist (rosiglitazone). The effects of PPARγ on cell migration and invasive activity were determined by wound healing assay and Matrigel invasive model in vitro, and in an orthotopic liver tumour metastatic model in mice.Results:Pronounced expression of PPARγ was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPARγ, rosiglitazone or Ad-PPARγ plus rosiglitazone, compared with control (Ad-LacZ). Such induction markedly suppressed HCC cell migration. Moreover, the invasiveness of MHCC97L and BEL-7404 cells infected with Ad-PPARγ, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPARγ and rosiglitazone showed an additive effect. Activation of PPARγ by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPARγ in HCC include upregulation of cell adhesion genes, E-cadherin and SYK (spleen tyrosine kinase), extracellular matrix regulator tissue inhibitors of metalloproteinase (TIMP) 3, tumour suppressor gene retinoblastoma 1, and downregulation of pro-metastatic genes MMP9 (matrix metallopeptidase 9), MMP13, HPSE (heparanase), and Hepatocyte growth factor (HGF). Direct transcriptional regulation of TIMP3, MMP9, MMP13, and HPSE by PPARγ was shown by ChIP-PCR. Conclusion: Peroxisome proliferator-activated receptor-gamma exerts an inhibitory effect on the invasive and metastatic potential of HCC in vitro and in vivo, and is thus, a target for the prevention and treatment of HCC metastases. © 2012 Cancer Research UK All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/159929
ISSN
2015 Impact Factor: 5.569
2015 SCImago Journal Rankings: 2.939
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorShen, Ben_HK
dc.contributor.authorChu, ESHen_HK
dc.contributor.authorZhao, Gen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorWu, CWen_HK
dc.contributor.authorCheng, JTYen_HK
dc.contributor.authorLi, Gen_HK
dc.contributor.authorNie, Yen_HK
dc.contributor.authorLo, CMen_HK
dc.contributor.authorTeoh, Nen_HK
dc.contributor.authorFarrell, GCen_HK
dc.contributor.authorSung, JJYen_HK
dc.contributor.authorYu, Jen_HK
dc.date.accessioned2012-08-16T05:59:37Z-
dc.date.available2012-08-16T05:59:37Z-
dc.date.issued2012en_HK
dc.identifier.citationBritish Journal Of Cancer, 2012, v. 106 n. 9, p. 1486-1494en_HK
dc.identifier.issn0007-0920en_HK
dc.identifier.urihttp://hdl.handle.net/10722/159929-
dc.description.abstractBackground: We have previously demonstrated that peroxisome proliferator-activated receptor (PPARγ) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPARγ on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms. Methods: Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPARγ (Ad-PPARγ) or Ad-lacZ and treated with or without PPARγ agonist (rosiglitazone). The effects of PPARγ on cell migration and invasive activity were determined by wound healing assay and Matrigel invasive model in vitro, and in an orthotopic liver tumour metastatic model in mice.Results:Pronounced expression of PPARγ was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPARγ, rosiglitazone or Ad-PPARγ plus rosiglitazone, compared with control (Ad-LacZ). Such induction markedly suppressed HCC cell migration. Moreover, the invasiveness of MHCC97L and BEL-7404 cells infected with Ad-PPARγ, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPARγ and rosiglitazone showed an additive effect. Activation of PPARγ by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPARγ in HCC include upregulation of cell adhesion genes, E-cadherin and SYK (spleen tyrosine kinase), extracellular matrix regulator tissue inhibitors of metalloproteinase (TIMP) 3, tumour suppressor gene retinoblastoma 1, and downregulation of pro-metastatic genes MMP9 (matrix metallopeptidase 9), MMP13, HPSE (heparanase), and Hepatocyte growth factor (HGF). Direct transcriptional regulation of TIMP3, MMP9, MMP13, and HPSE by PPARγ was shown by ChIP-PCR. Conclusion: Peroxisome proliferator-activated receptor-gamma exerts an inhibitory effect on the invasive and metastatic potential of HCC in vitro and in vivo, and is thus, a target for the prevention and treatment of HCC metastases. © 2012 Cancer Research UK All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjcen_HK
dc.relation.ispartofBritish Journal of Canceren_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectheparanaseen_HK
dc.subjecthepatocellular carcinoma metastasisen_HK
dc.subjectmatrix metallopeptidaseen_HK
dc.subjectPPARgen_HK
dc.subjecttissue inhibitors of metalloproteinaseen_HK
dc.subject.meshCarcinoma, Hepatocellular - drug therapy - metabolism - pathology-
dc.subject.meshLiver Neoplasms - drug therapy - metabolism - pathology-
dc.subject.meshLung Neoplasms - drug therapy - metabolism - secondary-
dc.subject.meshPPAR gamma - agonists - metabolism-
dc.subject.meshThiazolidinediones - pharmacology-
dc.titlePPARgamma inhibits hepatocellular carcinoma metastases in vitro and in miceen_HK
dc.typeArticleen_HK
dc.identifier.emailMan, K: kwanman@hkucc.hku.hken_HK
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hken_HK
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityLo, CM=rp00412en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/bjc.2012.130en_HK
dc.identifier.pmid22472882-
dc.identifier.pmcidPMC3341869-
dc.identifier.scopuseid_2-s2.0-84860251082en_HK
dc.identifier.hkuros202946en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84860251082&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume106en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1486en_HK
dc.identifier.epage1494en_HK
dc.identifier.isiWOS:000303383500005-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridShen, B=35084327200en_HK
dc.identifier.scopusauthoridChu, ESH=8631130300en_HK
dc.identifier.scopusauthoridZhao, G=13408962700en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridWu, CW=24342150800en_HK
dc.identifier.scopusauthoridCheng, JTY=7405939714en_HK
dc.identifier.scopusauthoridLi, G=55165534100en_HK
dc.identifier.scopusauthoridNie, Y=55199143100en_HK
dc.identifier.scopusauthoridLo, CM=7401771672en_HK
dc.identifier.scopusauthoridTeoh, N=16640481100en_HK
dc.identifier.scopusauthoridFarrell, GC=7102979833en_HK
dc.identifier.scopusauthoridSung, JJY=49061590200en_HK
dc.identifier.scopusauthoridYu, J=35351306800en_HK
dc.identifier.citeulike10543227-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats