Basic research and clinical approach of molecular therapy for liver cirrhosis and HCC

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Liver cirrhosis has been regarded to be irreversible end of fibrous scaring with no effective therapy up to now. We recently established a novel gene therapy approach for rat liver cirrhosis by HVJ-liposome mediated muscle-directed gene transfer of hepatocyte growth facor(HGF). We also reported novel gene therapy for hepatoma. In this study, we performed following several experiments to apply these molecular therapy for human liver cirrhosis and hepatoma : 1)analysis of detail mechanism of HGF mediated anti-fibrogenesis 2)bone marrow-derived cells participate in the remodeling process of liver fibrosis with HGF gene therapy 3)BMT mediated graft-versus-tumor effect against hepatoma.As the result of these experiments, we got much novel findings. HGF mediated anti-fibrogenesis was thought to act the enhancement of MMP expression by HGF rather than the suppression of TGFβ1 by activation of HGF in Kuppfer cells. When HGF acts in NK cell in vitro, TGFβ1 was suppressed in mRNA and protein level. Bone marrow-derived cells appeared to participate in the remodeling process of liver fibrosis and HGF gene delivery accelerated this recruitment. As the most of bone marrow-derived cell were detected as endothelial cells, reconstruction of blood vessels seemed significantly important for recovery process of liver fibrosis. BMT with HGF therapy markedly inhibited growth of hepatoma. Moreover, HGF ameliorates GVHD effect that is main side effect of BMT.These results suggested that these molecular therapy is capable for treatment of human liver cirrhosis and hepatoma.