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

肝硬变被认为是纤维性瘢痕不可逆转的终点，目前尚无有效的治疗方法。我们最近建立了一种新的基因治疗方法，通过脂质体介导的肌肉导向的肝细胞生长因子(HGF)基因转移来治疗大鼠肝硬变。我们还报道了新的肝癌基因治疗方法。在本研究中，我们进行了以下几个方面的实验：1)分析HGF介导的抗肝纤维化的具体机制；2)通过HGF基因治疗，骨髓来源的细胞参与了肝纤维化的重塑过程；3)BMT介导的移植物抗肿瘤作用。肝细胞生长因子介导的抗纤维化作用不是通过激活肝细胞生长因子来抑制转化生长因子β1的表达，而是增强肝细胞生长因子对基质金属蛋白酶的表达。当肝细胞生长因子在体外作用于NK细胞时，转化生长因子β-1在基因和蛋白水平均受到抑制。骨髓来源的细胞似乎参与了肝纤维化的重塑过程，而HGF基因的传递加速了这种募集。由于大部分骨髓源性细胞被检测为内皮细胞，血管重建对肝纤维化的恢复过程具有重要意义。BMT联合HGF治疗可明显抑制肝癌的生长。此外，HGF还能改善BMT的主要副作用之一的GVHD效应，这些结果表明这些分子疗法有能力治疗人的肝硬变和肝癌。

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.