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

File Download

content.pdf

Links for fulltext
(May Require Subscription)

Publisher Website: 10.1038/bjc.2012.130
Scopus: eid_2-s2.0-84860251082
PMID: 22472882

Supplementary

Citations:
- Scopus:
- Web of Science:
- PubMed Central:
Item Statistics (The Hub)
Appears in Collections:
- Surgery: Journal/Magazine Articles

Title	PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice
Authors	Shen, B2 5 Chu, ESH5 Zhao, G4 5 Man, K1 Wu, CW5 Cheng, JTY5 Li, G5 Nie, Y2 Lo, CM1 Teoh, N3 Farrell, GC3 Sung, JJY5 Yu, J5
Keywords	heparanase hepatocellular carcinoma metastasis matrix metallopeptidase PPARg tissue inhibitors of metalloproteinase
Issue Date	2012
Publisher	Nature 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?] DOI: http://dx.doi.org/10.1038/bjc.2012.130
Abstract	Background: 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.
Description	Open Access Article
ISSN	0007-0920 2011 Impact Factor: 5.042 2011 SCImago Journal Rankings: 0.561
DOI	http://dx.doi.org/10.1038/bjc.2012.130
PubMed Central ID	PMC3341869
References	References in Scopus

DC Field	Value
dc.contributor.author	Shen, B
dc.contributor.author	Chu, ESH
dc.contributor.author	Zhao, G
dc.contributor.author	Man, K
dc.contributor.author	Wu, CW
dc.contributor.author	Cheng, JTY
dc.contributor.author	Li, G
dc.contributor.author	Nie, Y
dc.contributor.author	Lo, CM
dc.contributor.author	Teoh, N
dc.contributor.author	Farrell, GC
dc.contributor.author	Sung, JJY
dc.contributor.author	Yu, J
dc.date.accessioned	2012-08-16T05:59:37Z
dc.date.available	2012-08-16T05:59:37Z
dc.date.issued	2012
dc.description.abstract	Background: 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.nature	published_or_final_version
dc.description	Open Access Article
dc.identifier.citation	British 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.citeulike	10543227
dc.identifier.doi	http://dx.doi.org/10.1038/bjc.2012.130
dc.identifier.epage	1494
dc.identifier.hkuros	202946
dc.identifier.issn	0007-0920 2011 Impact Factor: 5.042 2011 SCImago Journal Rankings: 0.561
dc.identifier.issue	9
dc.identifier.pmcid	PMC3341869
dc.identifier.pmid	22472882
dc.identifier.scopus	eid_2-s2.0-84860251082
dc.identifier.spage	1486
dc.identifier.uri	http://hdl.handle.net/10722/159929
dc.identifier.volume	106
dc.language	eng
dc.publisher	Nature Publishing Group. The Journal's web site is located at http://www.nature.com/bjc
dc.publisher.place	United Kingdom
dc.relation.ispartof	British Journal of Cancer
dc.relation.references	References in Scopus
dc.rights	Creative Commons: Attribution 3.0 Hong Kong License
dc.subject.mesh	Carcinoma, Hepatocellular - drug therapy - metabolism - pathology
dc.subject.mesh	Liver Neoplasms - drug therapy - metabolism - pathology
dc.subject.mesh	Lung Neoplasms - drug therapy - metabolism - secondary
dc.subject.mesh	PPAR gamma - agonists - metabolism
dc.subject.mesh	Thiazolidinediones - pharmacology
dc.subject	heparanase
dc.subject	hepatocellular carcinoma metastasis
dc.subject	matrix metallopeptidase
dc.subject	PPARg
dc.subject	tissue inhibitors of metalloproteinase
dc.title	PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice
dc.type	Article

<?xml encoding="utf-8" version="1.0"?><item><contributor.author>Shen, B</contributor.author><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><contributor.author>Sung, JJY</contributor.author><contributor.author>Yu, J</contributor.author><date.accessioned>2012-08-16T05:59:37Z</date.accessioned><date.available>2012-08-16T05:59:37Z</date.available><date.issued>2012</date.issued><identifier.citation>British Journal Of Cancer, 2012, v. 106 n. 9, p. 1486-1494</identifier.citation><identifier.issn>0007-0920</identifier.issn><identifier.uri>http://hdl.handle.net/10722/159929</identifier.uri><description>Open Access Article</description><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><language>eng</language><publisher>Nature Publishing Group. The Journal&apos;s web site is located at http://www.nature.com/bjc</publisher><relation.ispartof>British Journal of Cancer</relation.ispartof><rights>Creative Commons: Attribution 3.0 Hong Kong License</rights><subject>heparanase</subject><subject>hepatocellular carcinoma metastasis</subject><subject>matrix metallopeptidase</subject><subject>PPARg</subject><subject>tissue inhibitors of metalloproteinase</subject><subject.mesh>Carcinoma, Hepatocellular - drug therapy - metabolism - pathology</subject.mesh><subject.mesh>Liver Neoplasms - drug therapy - metabolism - pathology</subject.mesh><subject.mesh>Lung Neoplasms - drug therapy - metabolism - secondary</subject.mesh><subject.mesh>PPAR gamma - agonists - metabolism</subject.mesh><subject.mesh>Thiazolidinediones - pharmacology</subject.mesh><title>PPARgamma inhibits hepatocellular carcinoma metastases in vitro and in mice</title><type>Article</type><description.nature>published_or_final_version</description.nature><identifier.doi>10.1038/bjc.2012.130</identifier.doi><identifier.pmid>22472882</identifier.pmid><identifier.pmcid>PMC3341869</identifier.pmcid><identifier.scopus>eid_2-s2.0-84860251082</identifier.scopus><identifier.hkuros>202946</identifier.hkuros><relation.references>http://www.scopus.com/mlt/select.url?eid=2-s2.0-84860251082&amp;selection=ref&amp;src=s&amp;origin=recordpage</relation.references><identifier.volume>106</identifier.volume><identifier.issue>9</identifier.issue><identifier.spage>1486</identifier.spage><identifier.epage>1494</identifier.epage><publisher.place>United Kingdom</publisher.place><identifier.citeulike>10543227</identifier.citeulike><bitstream.url>http://hub.hku.hk/bitstream/10722/159929/1/content.pdf</bitstream.url></item>

Author Affiliations

The University of Hong Kong Li Ka Shing Faculty of Medicine
Guangzhou First Municipal People's Hospital
Australian National University Medical School
Inner Mongolia University China
Chinese University of Hong Kong