HEPATOCYTE GROWTH-FACTOR IN TRANSGENIC MICE

In order to clarify the function of hepatocyte growth factor (HGF) in vivo, we have developed transgenic mice expressing HGF in the liver. T he bromodeoxyuridine labelling indices in livers from HGF transgenic m ice were doubled, compared to those from wild type mice. Livers of HGF transgenic mice expressed high levels of c-myc, which was the consequ ence of increased transcription rates through the c-myc promoter. Afte r 70% partial hepatectomy, the livers of HGF transgenic mice recovered in halt the time needed for their normal siblings. Since we found tha t HGF inhibits growth of hepatocellular carcinoma (HCC) cells in vitro , we have made two kinds of double transgenic mice: HGF/TGF alpha and HGF/c-myc mice. The double transgenic mice expressing both HGF and TGF alpha had lower tumour yields, compared to TGF alpha transgenic mice. The HGF/c-myc double transgenic mice had a lower incidence of hepatoc ellular adenoma (HCA) and HCC in comparison with c-myc transgenic mice . In HGF/c-myc mice, there were more apoptotic cells and less mitotic cells than c-myc transgenic mice. These data indicate that HGF inhibit s growth and occurrence of HCC in vivo. We also found that HGF protect s liver from D-galactosamine (D-GalN)-induced injury. Hepatic prostagl andin E 2 (PGE2) contents in HGF transgenic mice were much higher than those in wild type mice, and were associated with hepatic HGF content s. An anti-HGF antibody inhibits production of PGE2 in liver after D-G alN administration. These data suggest that HGF protects liver from D- GalN-induced injury through increased liver PGE2 production. The data obtained from HGF transgenic mice suggests the possibility that HGF co uld be applicable for therapy of human liver diseases in the future.