Advertisement

Liver Cancer pp 333-342 | Cite as

Hepatocellular Carcinoma: Prognosis Using Hepatoma-Derived Growth Factor Immunohistochemistry

  • Hideji Nakamura
  • Kenya Yoshida
  • Yasuhiko Tomita
Chapter
Part of the Methods of Cancer Diagnosis, Therapy and Prognosis book series (HAYAT, volume 5)

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.

Keywords

Nuclear Localization Signal Fetal Hepatocyte PWWP Domain Pancreatic Ductal Cancer Differential Display Analysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abouzied, M.M., El-Tahir, H.M., Prenner, L., Haberlein, H., Gieselmann, V., and Franken, S. 2005. Hepatoma-derived growth factor. Significance of amino acid residues 81–100 in cell surface interaction and proliferative activity. J. Biol. Chem. 280: 10945–10954.PubMedCrossRefGoogle Scholar
  2. Dietz, F., Franken, S., Yoshida, K., Nakamura, H., Kappler, J., and Gieselmann, V. 2002. The family of hepatoma-derived growth factor proteins: characterization of a new member HRP-4 and classification of its subfamilies. Biochem. J. 366: 491–500.PubMedCrossRefGoogle Scholar
  3. Enomoto, H., Yoshida, K., Kishima, Y., Kinoshita, T., Yamamoto, M., Everett, A.D., Miyajima, A., and Nakamura, H. 2002. Hepatoma-derived growth factor is highly expressed in developing liver and promotes fetal hepatocyte proliferation. Hepatology 36: 1519–1527.PubMedGoogle Scholar
  4. Everett, A.D., Lobe, D.R., Matsumura, M.E., Nakamura, H., and McNamara, C.A. 2000. Hepatoma-derived growth factor stimulates smooth muscle cell growth and is expressed in vascular development. J. Clin. Invest. 105: 567–575.PubMedCrossRefGoogle Scholar
  5. Everett, A.D., Stoops, T., and McNamara, C.A. 2001. Nuclear targeting is required for hepato-ma-derived growth factor-stimulated mitogen-esis in vascular smooth muscle cells. J. Biol. Chem. 276: 37564–37568.PubMedCrossRefGoogle Scholar
  6. Everett, A.D., Narron, J.V., Stoops, T., Nakamura, H., and Tucker, A. 2004. Hepatoma-derived growth factor is a pulmonary endothelial cell-expressed angiogenic factor. Am. J. Physiol., Lung Cell. Mol. Physiol. 286: L1194–1201.CrossRefGoogle Scholar
  7. 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
  8. Hu, T.H., Huang, C.C., Liu, L.F., Lin, S.Y., Chang, H.W., Changchien, C.S., Lee, C.M., Chuang, J.H., and Tai, M.H. 2003. Expression of hepatoma-derived growth factor in hepatocel-lular carcinoma. Cancer 98: 1444–1456.PubMedCrossRefGoogle Scholar
  9. Huang, J.S., Chao, C.C., Su, T.L., Yeh, S.H., Chen, D.S., Chen, C.T., Chen, P.J., and Jou, Y.S. 2004. Diverse cellular transformation capability of overexpressed genes in human hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 315: 950–958.PubMedCrossRefGoogle Scholar
  10. Iwasaki, T., Nakagawa, K., Nakamura, H., Takada, T., Matsui, K., and Kawahara, K. 2005. Hepatoma-derived growth factor as a prognostic marker in completely resected non-small-cell lung cancer. Oncol. Rep. 13: 1075–1080.PubMedGoogle Scholar
  11. Izumoto, Y., Kuroda, T., Harada, H., Kishimoto, T., and Nakamura, H. 1997. Hepatoma-derived growth factor belongs to a gene family in mice showing significant homology in the amino terminus. Biochem. Biophys. Res. Commun. 238: 26–32.PubMedCrossRefGoogle Scholar
  12. 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
  13. 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
  14. 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
  15. 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
  16. Nakamura, H., Kambe, H., Egawa, T., Kimura, Y., Ito, H., Hayashi, E., Yamamoto, H., Sato, J., and Kishimoto, S. 1989. Partial purification and characterization of hepatoma-derived growth factor. Clin. Chim. Acta 183: 273–284.PubMedCrossRefGoogle Scholar
  17. Nakamura, H., Izumoto, Y., Kambe, H., Kuroda, T., Mori, T., Kawamura, K., Yamamoto, H., and Kishimoto, T. 1994. Molecular cloning of complementary DNA for a novel human hepatoma-derived growth factor. J. Biol. Chem. 269: 25143–25149.PubMedGoogle Scholar
  18. Nakamura, H., Yoshida, K., Ikegame, K., Kishima, Y., Uyama, H., and Enomoto, H. 2002. Antibodies against hepatoma-derived growth factor and mucosal repair in ulcerative colitis. J. Gastroenterol. 37 (Suppl. 14): 8–14.PubMedGoogle Scholar
  19. 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
  20. 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
  21. Oliver, J.A., and Al-Awqati, Q. 1998. An endothe-lial growth factor involved in rat renal development. J. Clin. Invest. 102: 1208–1219.PubMedCrossRefGoogle Scholar
  22. Ren, H., Tang, X., Lee, J.J., Feng, L., Everett, A.D., Hong, W.K., Khuri, F.R., and Mao, L. 2004. Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small cell lung cancer. J. Clin. Oncol. 22: 3230–3237.PubMedCrossRefGoogle Scholar
  23. 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
  24. 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
  25. Yoshida, K., Nakamura, H., Okuda, Y., Enomoto, H., Kishima, Y., Uyama, H., Ito, H., Hirasawa, T., Inagaki, S., and Kawase, I. 2003. Expression of hepatoma-derived growth factor in hepato-carcinogenesis. J. Gastroenterol. Hepatol. 18: 1293–1301.PubMedCrossRefGoogle Scholar
  26. 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
  27. Zhang, J., Ren, H., Yuan, P., Lang, W., Zhang, L., and Mao, L. 2006. Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells. Cancer Res. 66: 18–23.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2009

Authors and Affiliations

  • Hideji Nakamura
    • 1
  • Kenya Yoshida
    • 1
  • Yasuhiko Tomita
    • 1
  1. 1.Division of Heptobiliary and Pancreatic Medicine, Department of Internal MedicineHyogo College of MedicineMukogawacho, 1-IshinomiyaJapan

Personalised recommendations