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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Zan Shen
  • Fan Yang Zhen
  • Yi Gao
  • Cheng Li Ji
  • Xiao Chen Hai
  • Chiu Liu Ching
  • Ronnie T. P. Poon
  • Tat Fan Sheung
  • John M. Luk
  • Hung Sze Kong
  • Ping Li Tsai
  • Bao Gan Ren
  • Fu Kung Hsiang
  • Marie C. M. Lin

Detail(s)

Original languageEnglish
Pages (from-to)404-414
Journal / PublicationCancer Research
Volume68
Issue number2
Publication statusPublished - 15 Jan 2008
Externally publishedYes

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 G0-G1 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-NH2-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.

Citation Format(s)

The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma. / Shen, Zan; Zhen, Fan Yang; Gao, Yi; Ji, Cheng Li; Hai, Xiao Chen; Ching, Chiu Liu; Poon, Ronnie T. P.; Sheung, Tat Fan; Luk, John M.; Kong, Hung Sze; Tsai, Ping Li; Ren, Bao Gan; Ming, Liang He; Hsiang, Fu Kung; Lin, Marie C. M.

In: Cancer Research, Vol. 68, No. 2, 15.01.2008, p. 404-414.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review