Hepatocellular Carcinoma: Prognosis Using Hepatoma-Derived Growth Factor Immunohistochemistry
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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 the nucleus rather than in the cytoplasm (Everett et al., 2001). The gene-specific region of HDGF, at least the bipartite NLS sequence and both the N-and C-terminal neighboring portions, is essential for the mitogenic activity (Kishima et al., 2002a). Thus, HDGF exerts its proliferating activity via two different pathways: (1) via a putative plasma membrane-located HDGF receptor for which signaling depends on the hath region, resulting in MAP kinase activation, and (2) via targeting to the nucleus by NLS.
KeywordsNuclear Localization Signal Fetal Hepatocyte PWWP Domain Pancreatic Ductal Cancer Differential Display Analysis
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- Hayashi, E., Kuramatsu, Y., Okada, F., Fujimoto, M., Zhang, X., Kobayashi, M., Iizuka, N., Ueyama, Y., and Nakamura, K. 2005. Proteomic profiling for cancer progression: differential display analysis for the expression of intracellular proteins between regressive and progressive cancer cell lines. Proteomics 5: 1024–1032.PubMedCrossRefGoogle Scholar
- Kishima, Y., Yamamoto, H., Izumoto, Y., Yoshida, K., Enomoto, H., Yamamoto, M., Kuroda, T., Ito, H., Yoshizaki, K., and Nakamura, H. 2002a. Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus by nuclear localization signals. J. Biol. Chem. 277: 10315–10322.CrossRefGoogle Scholar
- Kishima, Y., Yoshida, K., Enomoto, H., Yamamoto, M., Kuroda, T., Okuda, Y., Uyama, H., and Nakamura, H. 2002b. Antisense oli-gonucleotides of hepatoma-derived growth factor (HDGF) suppress the proliferation of hepatoma cells. Hepatogastroenterology 49: 1639–1644.Google Scholar
- Lepourcelet, M., Tou, L., Cai L., Sawada, J., Lazar, A.J.F., Glickman, J.N., Williamson, J.A., Everett, A.D., Redston, M., Fox, E.A., Nakatani, Y., and Shivdasani, R.A. 2005. Insights into development mechanisms and cancers in the mammalian intesitine derived from serial analysis of gene expression and study of the hepatoma-derived growth factor (HDGF). Development 132: 415–427.PubMedCrossRefGoogle Scholar
- Mori, M., Morishita, H., Nakamura, H., Matsuoka, H., Yoshida, K., Kishima, Y., Zhou, Z., Kida, H., Funakoshi, T., Goya, S., Yoshida, M., Kumagai, T., Tachibana, I., Yamamoto, Y., Kawase, I., and Hayashi, S. 2004. Hepatoma-derived growth factor is involved in lung remodeling by stimulating epithelial growth. Am. J. Respir. Cell Mol. Biol. 30: 459–469.PubMedCrossRefGoogle Scholar
- Nakamura, H., and Hada, T. 2004. Hepatoma-derived growth factor in ontogeny and tumori-genesis. Recent Res. Devel. Biophys. Biochem. 4: 17–27.Google Scholar
- Okuda, Y., Nakamura, H., Yoshida, K., Enomoto, H., Uyama, H., Hirotani, T., Funamoto, M., Ito, H., Everett, A.D., Hada, T., and Kawase, I. 2003. Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor. Cancer Sci. 94: 1034–1041.PubMedCrossRefGoogle Scholar
- Uyama, H., Tomita, Y., Nakamura, H., Nakamori, S., Zhang, B., Hoshida, Y., Enomoto, H., Okuda, Y., Sakon, M., Aozasa, K., Kawase, I., Hayashi, N., and Monden, M. 2006. Hepatoma-derived growth factor is a novel prognostic factor for patients with pancreatic cancer. Clin. Cancer Res. 12: 6043–6048.PubMedCrossRefGoogle Scholar
- Yamamoto, S., Yasuhiko, T., Hoshida, Y., Takiguchi, S., Fujiwara, Y., Yasuda, T., Doki, Y., Yoshida, K., Aozasa, K., Nakamura, H., and Monden, M. 2006. Expression of hepatoma-derived growth factor is correlated with lymph node metastasis and prognosis of gastric carcinoma. Clin. Cancer Res. 12: 117–122.PubMedCrossRefGoogle Scholar
- Yoshida, K., Tomita, T., Okuda, Y., Yamamoto, S., Enomoto, H., Uyama, H., Ito, H., Hoshida, Y., Aozasa, S., Nagano, H., Sakon, M., Kawase, I., Monden, M., and Nakamura, H. 2006. Hepatoma-derived growth factor is a novel prognostic factor for hepatocellular carcinoma. Ann. Surg. Oncol. 13: 159–167.PubMedCrossRefGoogle Scholar