Kringle 1 Domain of Human Hepatocyte Growth Factor (HGFK1) Inhibits the Growth and Metastasis of Hepatocellular Carcinoma in Rats

Abstract

Objective: We have previously shown that recombinant protein of kringle 1 domain of human hepatocyte growth factor (HGFK1) inhibits the proliferation of bovine aortic endothelial (BAE) cells. Here we investigate the in vivo efficacy of long term expression of HGFK1 in cancer gene therapy for hepatocellular carcinoma (HCC) using the adenoassociated virus (serotype 2) carrying the HGFK1 gene (rAAV-HGFK1). Methods: Preclinical animal studies were conducted using an established orthotopic Buffalo rat HCC model. HCC was induced by injection of 1.0×106 rat hepatoma cells, McA-RH7777, into the left lobe of the liver. Ten days after tumor cell inoculation, surgeries were performed to confirm the tumor formation. Then rAAV-HGFKl (1.2×1012 v.p.), rAAV-EGFP (1.2×1012 v.p.) or PBS were injected directly into the tumor nodule (0.2×1012 v.p.) followed by portal vein (1.0×1012 v.p.) injection. Results: We first showed that infection by rAAV-HGFKl produced significant anti-angiogenesis effect as demonstrated by reduced proliferation and microvascular tube formation of mouse microvascular endothelial cells in vitro in the cell culture system. The in vivo efficacy of rAAV-HGFK1 was then evaluated in the rat model of HCC. Results from our study demonstrated for the first time that a long term expression of HGFK1 significantly prolonged the median survival rate of the HCC bearing rats from 30 days to 49 days. More importantly rAAV-HGFK1 inhibited tumor growth and completely prevented lung and peritoneal metastasis. Conclusion: Long term expression of HGFK1 might be a novel promising treatment for HCC and other cancers.