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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

TitleUp-regulation of TIMP-1 by genipin inhibits MMP-2 activities and suppresses the metastatic potential of human hepatocellular carcinoma
Authors
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
Citation
PLoS One, 2012, v. 7 n. 9, article no. e46318 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/169170
ISSN
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
PubMed Central ID
ISI Accession Number ID
References

 

Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
DC FieldValueLanguage
dc.contributor.authorWang, Nen_HK
dc.contributor.authorZhu, Men_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorZhang, Zen_HK
dc.contributor.authorFeng, Yen_HK
dc.date.accessioned2012-10-18T08:45:07Z-
dc.date.available2012-10-18T08:45:07Z-
dc.date.issued2012en_HK
dc.identifier.citationPLoS One, 2012, v. 7 n. 9, article no. e46318en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/169170-
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.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS Oneen_HK
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 carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.emailWang, N: ckwang@hku.hken_HK
dc.identifier.emailZhu, M: mfzhu@hku.hken_HK
dc.identifier.emailTsao, SW: gswtsao@hku.hken_HK
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.emailZhang, Z: zhangzj@hkucc.hku.hk-
dc.identifier.emailFeng, Y: yfeng@hku.hk-
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityZhang, Z=rp01297en_HK
dc.identifier.authorityFeng, Y=rp00466en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1371/journal.pone.0046318en_HK
dc.identifier.pmid23029478-
dc.identifier.pmcidPMC3461024-
dc.identifier.scopuseid_2-s2.0-84867000366en_HK
dc.identifier.hkuros216751en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84867000366&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume7en_HK
dc.identifier.issue9, article no. e46318en_HK
dc.identifier.isiWOS:000309973900133-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridFeng, Y=24467969600en_HK
dc.identifier.scopusauthoridZhang, Z=8061473900en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridTsao, SW=55311525100en_HK
dc.identifier.scopusauthoridZhu, M=36706949300en_HK
dc.identifier.scopusauthoridWang, N=55359687200en_HK

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