Hepatocellular Carcinoma: Prognosis Using Hepatoma-Derived Growth Factor Immunohistochemistry

Abstract

Hepatoma-derived growth factor (HDGF) is a heparin-binding protein purified from the conditioned medium of the human well-differentiated hepatocellular carcinoma (HCC) cell line, HuH-7, which can proliferate autonomously in a serum-free chemically-defined medium; this factor is highly expressed in several cancer cells (Nakamura et al., 1989, 1994; Mori et al., 2004). Hepatoma-derived growth factor is an acidic 26 kDa protein consisting of 230 amino acids with no hydrophobic signal sequence in its N-terminus, and it has a high affinity to the glycosaminoglycans heparin and heparan sulphate (Nakamura et al., 1994; Dietz et al., 2002). Exogenously supplied HDGF stimulates the proliferation of fibroblasts, endothelial cells, vascular smooth muscle cells, pulmonary epithelial cells and hepatocytes, as well as HCC, lung cancer, and colon cancer cells. A possible receptor-binding site is estimated to be residing at amino acid residues 81–100 within the hath region (described below) (Abouzied et al., 2005). Indeed, exogenous HDGF stimulates the Erk phosphorylation in endothelial cells (Everett et al., 2004). Hepatoma-derived growth factor is a major member of the HDGF family of proteins which consists of HDGF and five HDGF-related proteins (HRP) (Izumoto et al., 1997; Dietz et al., 2002). The N-terminal region of HDGF is highly conserved among the other five HDGF-related proteins (HRP), and this region is called hath (homologous to the amino terminus of HDGF) region, which contains the PWWP domain (Izumoto et al., 1997). The HDGF family members are characterized based on whether they contain the hath region and nuclear localization signals (NLS) in their gene-specific regions and are targeting to the nucleus (Nakamura and Hada, 2004). Hepatoma-derived growth factor contains two nuclear localization signals (NLS) in the molecule of HDGF; the first functional nuclear localization signal (NLS1) is in the hath region and the second NLS (NLS2) is in gene-specific regions of the C-terminal region (Kishima et al., 2002a). Hepatoma-derived growth factor can traffic to the nucleus using these NLSs, especially the NLS2 in its gene-specific region, and this factor is dominantly localized in 26 Hepatocellular Carcinoma: Prognosis Using Hepatoma-Derived Growth Factor Immunohistochemistry