Article: Up-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma

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Title	Up-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma
Authors	Wang, N1 Zhu, M1 Tsao, SW1 Man, K1 Zhang, Z1 Feng, Y1
Keywords	Animal experiment Cancer cell culture Cell invasion Cell migration Cell motility
Issue Date	2012
Publisher	Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation	PLoS One, 2012, v. 7 n. 9, article no. e46318 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0046318
Abstract	AIM OF THE STUDY: Hepatocellular carcinoma is one of the most malignant human cancers with high metastatic potential. The aim of this study is to investigate the anti-metastatic effect of genipin and its underlying mechanism. EXPERIMENTAL APPROACH: The anti-metastatic potential of genipin was evaluated by both cell and animal model. Wound healing and invasion chamber assays were introduced to examine the anti-migration and anti-invasion action of genipin in human hepatocellular carcinoma cell HepG2 and MHCC97L; orthotopical implantation model was used for in vivo evaluation. Gelatin Zymography, Immunoblotting, quantitative real-time polymerase chain reaction and ELISA assays were used to study the mechanisms underlying genipin's anti-metastatic effect. KEY RESULTS: Genipin suppresses the motility and invasiveness of HepG2 and MHCC97L at non-toxic doses, which may be correlated to the inhibition of genipin on MMP-2 activities in the cells. No significant reduced expression of MMP-2 was observed either at mRNA or at protein level. Furthermore, genipin could specifically up-regulate the expression of TIMP-1, the endogenous inhibitor of MMP-2 activities. Silencing of TIMP-1 by RNA interference abolishes genipin's anti-metastaic effect. Activation of p38 MAPK signaling was observed in genipin-treated cells, which is responsible for the TIMP-1 overexpression and MMP-2 inhibition. Presence of SB202190, the p38 MAPK inhibitor, attenuates the anti-metastatic potential of genipin in hepatocellular carcinoma. Orthotopical implantation model showed that genipin could suppress the intrahepatic metastatic as well as tumor expansion in liver without exhibiting potent toxicity. CONCLUSION: Our findings demonstrated the potential of genipin in suppressing hepatocellular carcinoma metastasis, and p38/TIMP-1/MMP-2 pathway may be involved as the key mechanism of its anti-metastasis effect.
ISSN	1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519
DOI	http://dx.doi.org/10.1371/journal.pone.0046318
PubMed Central ID	PMC3461024
References	References in Scopus

DC Field	Value
dc.contributor.author	Wang, N
dc.contributor.author	Zhu, M
dc.contributor.author	Tsao, SW
dc.contributor.author	Man, K
dc.contributor.author	Zhang, Z
dc.contributor.author	Feng, Y
dc.date.accessioned	2012-10-18T08:45:07Z
dc.date.available	2012-10-18T08:45:07Z
dc.date.issued	2012
dc.description.abstract	AIM OF THE STUDY: Hepatocellular carcinoma is one of the most malignant human cancers with high metastatic potential. The aim of this study is to investigate the anti-metastatic effect of genipin and its underlying mechanism. EXPERIMENTAL APPROACH: The anti-metastatic potential of genipin was evaluated by both cell and animal model. Wound healing and invasion chamber assays were introduced to examine the anti-migration and anti-invasion action of genipin in human hepatocellular carcinoma cell HepG2 and MHCC97L; orthotopical implantation model was used for in vivo evaluation. Gelatin Zymography, Immunoblotting, quantitative real-time polymerase chain reaction and ELISA assays were used to study the mechanisms underlying genipin's anti-metastatic effect. KEY RESULTS: Genipin suppresses the motility and invasiveness of HepG2 and MHCC97L at non-toxic doses, which may be correlated to the inhibition of genipin on MMP-2 activities in the cells. No significant reduced expression of MMP-2 was observed either at mRNA or at protein level. Furthermore, genipin could specifically up-regulate the expression of TIMP-1, the endogenous inhibitor of MMP-2 activities. Silencing of TIMP-1 by RNA interference abolishes genipin's anti-metastaic effect. Activation of p38 MAPK signaling was observed in genipin-treated cells, which is responsible for the TIMP-1 overexpression and MMP-2 inhibition. Presence of SB202190, the p38 MAPK inhibitor, attenuates the anti-metastatic potential of genipin in hepatocellular carcinoma. Orthotopical implantation model showed that genipin could suppress the intrahepatic metastatic as well as tumor expansion in liver without exhibiting potent toxicity. CONCLUSION: Our findings demonstrated the potential of genipin in suppressing hepatocellular carcinoma metastasis, and p38/TIMP-1/MMP-2 pathway may be involved as the key mechanism of its anti-metastasis effect.
dc.description.nature	Link_to_subscribed_fulltext
dc.identifier.citation	PLoS One, 2012, v. 7 n. 9, article no. e46318 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0046318
dc.identifier.doi	http://dx.doi.org/10.1371/journal.pone.0046318
dc.identifier.hkuros	212271
dc.identifier.issn	1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519
dc.identifier.issue	9, article no. e46318
dc.identifier.pmcid	PMC3461024
dc.identifier.pmid	23029478
dc.identifier.scopus	eid_2-s2.0-84867000366
dc.identifier.uri	http://hdl.handle.net/10722/169170
dc.identifier.volume	7
dc.language	eng
dc.publisher	Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
dc.publisher.place	United States
dc.relation.ispartof	PLoS One
dc.relation.references	References in Scopus
dc.subject	Animal experiment
dc.subject	Cancer cell culture
dc.subject	Cell invasion
dc.subject	Cell migration
dc.subject	Cell motility
dc.title	Up-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma
dc.type	Article

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Author Affiliations

The University of Hong Kong Li Ka Shing Faculty of Medicine