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

HDGF（肝癌衍生生长因子）是一种肝素结合蛋白，已从hh -7肝癌细胞的条件培养基中纯化出来。最近的研究表明HDGF参与肾脏和心血管系统的发育。在本研究中，我们探讨了HDGF也参与肝脏发育和再生的可能性。HDGF在妊娠中期胎儿肝脏中表达强烈，临近出生时表达明显降低。它主要在未成熟肝细胞中表达，并随着肝细胞的分化而显著降低。重组HDGF可促进原代培养的胎儿肝细胞的生长。腺病毒法导入HDGF反义cDNA可显著抑制胎儿肝细胞的增殖。外源HDGF恢复了HDGF反义病毒的生长抑制作用。HDGF表达在肝部分切除和ccl_4肝损伤后的肝再生中被诱导。在两种模型中，HDGF的表达均在DNA合成高峰之前被诱导。再生肝中HDGF基因主要在实质肝细胞中表达。这些结果表明，HDGF作为一种自分泌因子在肝脏发育和再生中起重要作用，特别是在肝细胞增殖中。接下来，我们研究了HDGF在肝细胞癌变中的作用。在人类样本中，与邻近的非癌组织相比，HCC中HDGF mRNA和蛋白的表达升高。在啮齿类动物肝癌模型中，Western blotting和免疫组化结果显示，HDGF在FLS小鼠或cdaa喂养大鼠发生的HCC中比非癌组织表达更丰富。在FLS小鼠从出生开始的衰老过程中，HDGF mRNA表达的增加早于HCC的发生，HDGF高表达灶（HEF）也出现在HCC发生前阶段。苏木精-伊红染色不能将HEF与正常肝细胞区分开来。这些发现提示HDGF将成为癌前病变的标志物，HDGF作为肝癌发生的重要因素之一在肝癌发生中发挥重要作用。少

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