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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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TitleUp-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma
 
AuthorsWang, N1
Zhu, M1
Tsao, SW1 1
Man, K1 1
Zhang, Z1
Feng, Y1
 
KeywordsAnimal experiment
Cancer cell culture
Cell invasion
Cell migration
Cell motility
 
Issue Date2012
 
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
CitationPLoS One, 2012, v. 7 n. 9, article no. e46318 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0046318
 
AbstractAIM 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.
 
ISSN1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
DOIhttp://dx.doi.org/10.1371/journal.pone.0046318
 
PubMed Central IDPMC3461024
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorWang, N
 
dc.contributor.authorZhu, M
 
dc.contributor.authorTsao, SW
 
dc.contributor.authorMan, K
 
dc.contributor.authorZhang, Z
 
dc.contributor.authorFeng, Y
 
dc.date.accessioned2012-10-18T08:45:07Z
 
dc.date.available2012-10-18T08:45:07Z
 
dc.date.issued2012
 
dc.description.abstractAIM 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.natureLink_to_subscribed_fulltext
 
dc.identifier.citationPLoS One, 2012, v. 7 n. 9, article no. e46318 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0046318
 
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0046318
 
dc.identifier.hkuros216751
 
dc.identifier.issn1932-6203
2012 Impact Factor: 3.73
2012 SCImago Journal Rankings: 1.512
 
dc.identifier.issue9, article no. e46318
 
dc.identifier.pmcidPMC3461024
 
dc.identifier.pmid23029478
 
dc.identifier.scopuseid_2-s2.0-84867000366
 
dc.identifier.urihttp://hdl.handle.net/10722/169170
 
dc.identifier.volume7
 
dc.languageeng
 
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
 
dc.publisher.placeUnited States
 
dc.relation.ispartofPLoS One
 
dc.relation.referencesReferences in Scopus
 
dc.subjectAnimal experiment
 
dc.subjectCancer cell culture
 
dc.subjectCell invasion
 
dc.subjectCell migration
 
dc.subjectCell motility
 
dc.titleUp-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma
 
dc.typeArticle
 
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<contributor.author>Zhu, M</contributor.author>
<contributor.author>Tsao, SW</contributor.author>
<contributor.author>Man, K</contributor.author>
<contributor.author>Zhang, Z</contributor.author>
<contributor.author>Feng, Y</contributor.author>
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<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&apos;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&apos;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.</description.abstract>
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine