Roles of hepatoma-derived growth factor (HDGF) on liver development, regeneration and hepatocellular carcinogenesis

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HDGF (Hepatoma-derived growth factor) is a heparin-binding protein, which has been purified from the conditioned media of HuH-7 hepatoma cells. Recent studies have suggested the involvement of HDGF in the development of the kidney and cardiovascular systems. In the present study, we investigated the possibility that HDGF was also involved in the liver development and regeneration. HDGF expression was strongly detected in the fetal liver of the mid-gestation stage and was markedly decreased near birth. Its expression was mainly detected in immature hepatocytes and was remarkably decreased with their differentiation. Administration of recombinant HDGF enhanced the growth of primary cultured fetal hepatocytes. Adenovirally introduction of HDGF antisense cDNA into the fetal hepatocytes significantly suppressed their proliferation. The growth inhibitory effects of the HDGF antisense virus were recovered by exogenous HDGF. HDGF expression was induced in liver regeneration after partial hepat … More ectomy and CCl_4-induced liver damage. In both models, HDGF expression was induced before the peak of DNA synthesis. Expression of the HDGF gene in the regenerating liver was dominantly detected in parenchymal hepatocytes. These findings suggest that HDGF plays an important role in the liver development and regeneration as an autocrine factor, especially in the hepatocyte proliferation. Next, we investigated the roles of HDGF on hepatocellular carcinogenesis. In human samples, the expression of HDGF mRNA and proteins were elevated in HCC as compared to the adjacent non-cancerous tissues. In rodent models of hepatic carcinogenesis, HDGF expressed more abundantly in HCC, which developed in FLS mouse or CDAA-feeding rat than the non-cancerous tissues by Western blotting and immunohistochemistry. During the aging from the birth, HDGF mRNA expression started to increase earlier than the development of HCC in FLS mouse, and also HDGF-highly expressing foci (HEF) appeared in the stage before the development of HCC. The HEF could not be distinct from the normal hepatocytes by Hematoxylin-Eosine staining. These findings suggest that HDGF would become a marker for precancerous lesions and that HDGF play an important role on hepatic carcinogenesis as one of the important factors. Less