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Article: The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma
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TitleThe kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma
 
AuthorsShen, Z2
Zhen, FY2
Gao, Y2
Ji, CL3
Hai, XC1
Ching, CL2
Poon, RTP2
Sheung, TF2
Luk, JM2
Kong, HS2
Tsai, PL4
Ren, BG4
Ming, LH5
Hsiang, FK5
Lin, MCM2
 
Issue Date2008
 
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
 
CitationCancer Research, 2008, v. 68 n. 2, p. 404-414 [How to Cite?]
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-07-2081
 
AbstractThe kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAVHGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0-G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and β fibroblast growth factor (bFGF)/β fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. ©2008 American Association for Cancer Research.
 
ISSN0008-5472
2013 Impact Factor: 9.284
2013 SCImago Journal Rankings: 5.627
 
DOIhttp://dx.doi.org/10.1158/0008-5472.CAN-07-2081
 
ISI Accession Number IDWOS:000252503800011
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorShen, Z
 
dc.contributor.authorZhen, FY
 
dc.contributor.authorGao, Y
 
dc.contributor.authorJi, CL
 
dc.contributor.authorHai, XC
 
dc.contributor.authorChing, CL
 
dc.contributor.authorPoon, RTP
 
dc.contributor.authorSheung, TF
 
dc.contributor.authorLuk, JM
 
dc.contributor.authorKong, HS
 
dc.contributor.authorTsai, PL
 
dc.contributor.authorRen, BG
 
dc.contributor.authorMing, LH
 
dc.contributor.authorHsiang, FK
 
dc.contributor.authorLin, MCM
 
dc.date.accessioned2010-09-06T06:14:39Z
 
dc.date.available2010-09-06T06:14:39Z
 
dc.date.issued2008
 
dc.description.abstractThe kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAVHGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G 0-G 1 phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and β fibroblast growth factor (bFGF)/β fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH 2-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC. ©2008 American Association for Cancer Research.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationCancer Research, 2008, v. 68 n. 2, p. 404-414 [How to Cite?]
DOI: http://dx.doi.org/10.1158/0008-5472.CAN-07-2081
 
dc.identifier.doihttp://dx.doi.org/10.1158/0008-5472.CAN-07-2081
 
dc.identifier.epage414
 
dc.identifier.hkuros139937
 
dc.identifier.isiWOS:000252503800011
 
dc.identifier.issn0008-5472
2013 Impact Factor: 9.284
2013 SCImago Journal Rankings: 5.627
 
dc.identifier.issue2
 
dc.identifier.openurl
 
dc.identifier.pmid18199534
 
dc.identifier.scopuseid_2-s2.0-39049146233
 
dc.identifier.spage404
 
dc.identifier.urihttp://hdl.handle.net/10722/69544
 
dc.identifier.volume68
 
dc.languageeng
 
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofCancer Research
 
dc.relation.referencesReferences in Scopus
 
dc.titleThe kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma
 
dc.typeArticle
 
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Author Affiliations
  1. Taizhou Hospital
  2. The University of Hong Kong
  3. Zhejiang University
  4. Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences Chinese Academy of Sciences
  5. Chinese University of Hong Kong