title: The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma.
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, rAAV-HGFK1 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 beta fibroblast growth factor (bFGF)/beta 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.
authors.affiliation: Institute of Molecular Biology, Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Shen
authors.forename: Zhen Fan
authors.initials: ZF
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Ji Cheng
authors.initials: JC
authors.lastname: Li
authors.forename: Hai Xiao
authors.initials: HX
authors.lastname: Chen
authors.forename: Ching Chiu
authors.initials: CC
authors.lastname: Liu
authors.forename: Ronnie T P
authors.initials: RT
authors.lastname: Poon
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
authors.forename: Kong Hung
authors.initials: KH
authors.lastname: Sze
authors.forename: Tsai Ping
authors.initials: TP
authors.lastname: Li
authors.forename: Ren Bao
authors.initials: RB
authors.lastname: Gan
authors.forename: Ming Liang
authors.initials: ML
authors.lastname: He
authors.forename: Hsiang Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Marie C M
authors.initials: MC
authors.lastname: Lin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D015316:Genetic Therapy; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D018082:Kringles / Q000235:genetics* / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D009362:Neoplasm Metastasis; D051381:Rats; D011915:Rats, Inbred BUF; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016019:Survival Analysis
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017468:Receptors, Fibroblast Growth Factor; D017228:Hepatocyte Growth Factor; C483803:Egfr protein, rat; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor