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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
Man, K1
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
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
 
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
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
 
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