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Article: PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice
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TitlePPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice
 
AuthorsShen, B6 2
Chu, ESH6
Zhao, G6 5
Man, K1
Wu, CW6
Cheng, JTY6
Li, G6
Nie, Y2
Lo, CM1
Teoh, N3
Farrell, GC3
Sung, JJY6
Yu, J6 4
 
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
 
CitationBritish Journal Of Cancer, 2012, v. 106 n. 9, p. 1486-1494 [How to Cite?]
DOI: http://dx.doi.org/10.1038/bjc.2012.130
 
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.
 
DescriptionOpen Access Article
 
ISSN0007-0920
2012 Impact Factor: 5.082
2012 SCImago Journal Rankings: 2.311
 
DOIhttp://dx.doi.org/10.1038/bjc.2012.130
 
PubMed Central IDPMC3341869
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorShen, B
 
dc.contributor.authorChu, ESH
 
dc.contributor.authorZhao, G
 
dc.contributor.authorMan, K
 
dc.contributor.authorWu, CW
 
dc.contributor.authorCheng, JTY
 
dc.contributor.authorLi, G
 
dc.contributor.authorNie, Y
 
dc.contributor.authorLo, CM
 
dc.contributor.authorTeoh, N
 
dc.contributor.authorFarrell, GC
 
dc.contributor.authorSung, JJY
 
dc.contributor.authorYu, J
 
dc.date.accessioned2012-08-16T05:59:37Z
 
dc.date.available2012-08-16T05:59:37Z
 
dc.date.issued2012
 
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.
 
dc.description.naturepublished_or_final_version
 
dc.descriptionOpen Access Article
 
dc.identifier.citationBritish Journal Of Cancer, 2012, v. 106 n. 9, p. 1486-1494 [How to Cite?]
DOI: http://dx.doi.org/10.1038/bjc.2012.130
 
dc.identifier.citeulike10543227
 
dc.identifier.doihttp://dx.doi.org/10.1038/bjc.2012.130
 
dc.identifier.epage1494
 
dc.identifier.hkuros202946
 
dc.identifier.issn0007-0920
2012 Impact Factor: 5.082
2012 SCImago Journal Rankings: 2.311
 
dc.identifier.issue9
 
dc.identifier.pmcidPMC3341869
 
dc.identifier.pmid22472882
 
dc.identifier.scopuseid_2-s2.0-84860251082
 
dc.identifier.spage1486
 
dc.identifier.urihttp://hdl.handle.net/10722/159929
 
dc.identifier.volume106
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofBritish Journal of Cancer
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
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.subjectheparanase
 
dc.subjecthepatocellular carcinoma metastasis
 
dc.subjectmatrix metallopeptidase
 
dc.subjectPPARg
 
dc.subjecttissue inhibitors of metalloproteinase
 
dc.titlePPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice
 
dc.typeArticle
 
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<contributor.author>Chu, ESH</contributor.author>
<contributor.author>Zhao, G</contributor.author>
<contributor.author>Man, K</contributor.author>
<contributor.author>Wu, CW</contributor.author>
<contributor.author>Cheng, JTY</contributor.author>
<contributor.author>Li, G</contributor.author>
<contributor.author>Nie, Y</contributor.author>
<contributor.author>Lo, CM</contributor.author>
<contributor.author>Teoh, N</contributor.author>
<contributor.author>Farrell, GC</contributor.author>
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<description.abstract>Background: We have previously demonstrated that peroxisome proliferator-activated receptor (PPAR&#947;) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPAR&#947; on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms. Methods: Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPAR&#947; (Ad-PPAR&#947;) or Ad-lacZ and treated with or without PPAR&#947; agonist (rosiglitazone). The effects of PPAR&#947; 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 PPAR&#947; was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPAR&#947;, rosiglitazone or Ad-PPAR&#947; 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-PPAR&#947;, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPAR&#947; and rosiglitazone showed an additive effect. Activation of PPAR&#947; by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPAR&#947; 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 PPAR&#947; 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. &#169; 2012 Cancer Research UK All rights reserved.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Guangzhou First Municipal People's Hospital
  3. Australian National University Medical School
  4. Prince of Wales Hospital Hong Kong
  5. Inner Mongolia University China
  6. Chinese University of Hong Kong