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Article: The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma

TitleThe kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2008, v. 68 n. 2, p. 404-414 How to Cite?
Abstract
The 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.
Persistent Identifierhttp://hdl.handle.net/10722/69544
ISSN
2013 Impact Factor: 9.284
2013 SCImago Journal Rankings: 5.627
ISI Accession Number ID
References

 

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
DC FieldValueLanguage
dc.contributor.authorShen, Zen_HK
dc.contributor.authorZhen, FYen_HK
dc.contributor.authorGao, Yen_HK
dc.contributor.authorJi, CLen_HK
dc.contributor.authorHai, XCen_HK
dc.contributor.authorChing, CLen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorSheung, TFen_HK
dc.contributor.authorLuk, JMen_HK
dc.contributor.authorKong, HSen_HK
dc.contributor.authorTsai, PLen_HK
dc.contributor.authorRen, BGen_HK
dc.contributor.authorMing, LHen_HK
dc.contributor.authorHsiang, FKen_HK
dc.contributor.authorLin, MCMen_HK
dc.date.accessioned2010-09-06T06:14:39Z-
dc.date.available2010-09-06T06:14:39Z-
dc.date.issued2008en_HK
dc.identifier.citationCancer Research, 2008, v. 68 n. 2, p. 404-414en_HK
dc.identifier.issn0008-5472en_HK
dc.identifier.urihttp://hdl.handle.net/10722/69544-
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.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_HK
dc.relation.ispartofCancer Researchen_HK
dc.titleThe kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0008-5472&volume=68&spage=404&epage=414&date=2008&atitle=The+Kringle+1+Domain+of+Hepatocyte+Growth+Factor+Has+Antiangiogenic+and+Antitumor+Cell+Effects+on+Hepatocellular+Carcinomaen_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.emailLuk, JM: jmluk@hkucc.hku.hken_HK
dc.identifier.emailLin, MCM: mcllin@hkucc.hku.hken_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.identifier.authorityLuk, JM=rp00349en_HK
dc.identifier.authorityLin, MCM=rp00746en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-07-2081en_HK
dc.identifier.pmid18199534-
dc.identifier.scopuseid_2-s2.0-39049146233en_HK
dc.identifier.hkuros139937en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-39049146233&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume68en_HK
dc.identifier.issue2en_HK
dc.identifier.spage404en_HK
dc.identifier.epage414en_HK
dc.identifier.isiWOS:000252503800011-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridShen, Z=35759640300en_HK
dc.identifier.scopusauthoridZhen, FY=14018809600en_HK
dc.identifier.scopusauthoridGao, Y=9278971300en_HK
dc.identifier.scopusauthoridJi, CL=23977814000en_HK
dc.identifier.scopusauthoridHai, XC=23978167700en_HK
dc.identifier.scopusauthoridChing, CL=23977512400en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK
dc.identifier.scopusauthoridSheung, TF=6506234707en_HK
dc.identifier.scopusauthoridLuk, JM=7006777791en_HK
dc.identifier.scopusauthoridKong, HS=7201353072en_HK
dc.identifier.scopusauthoridTsai, PL=23978823700en_HK
dc.identifier.scopusauthoridRen, BG=23978490300en_HK
dc.identifier.scopusauthoridMing, LH=13612836600en_HK
dc.identifier.scopusauthoridHsiang, FK=16306692200en_HK
dc.identifier.scopusauthoridLin, MCM=7404816359en_HK

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