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Tumor Biology

, Volume 36, Issue 1, pp 353–364 | Cite as

Hepatoma-derived growth factor: a novel prognostic biomarker in intrahepatic cholangiocarcinoma

  • Sen Guo
  • Hong-da Liu
  • Yan-feng Liu
  • Lei Liu
  • Qiang Sun
  • Xi-jun Cui
Research Article

Abstract

Hepatoma-derived growth factor (HDGF) is an acidic heparin-binding protein involved in tumor progression and poor prognosis of kinds of cancers. Aimed at investigating the functions of HDGF in intrahepatic cholangiocarcinoma (IHCC), we detected the expression of HDGF by immunohistochemistry in 83 patients. Associations of HDGF with clinicopathologic features, microvascular density (MVD), and overall survival rates were further analyzed by Chi-square method, univariate or multivariate analysis. HDGF functions in IHCC proliferation, invasion, and angiogenesis were detected by MTT, transwell, and tube formation assays, respectively. As a result, we found that HDGF-positive expression rate in IHCC was 51.8 % (43/83) in IHCC. HDGF expression was significantly correlated to MVD (P = 0.031), lymphatic invasion (P = 0.030), distant metastasis (P = 0.002), and TNM stage (P = 0.037). HDGF was further identified as an independent prognostic factor in IHCC with Kaplan-Meier method (P = 0.003) and Cox-regression model (P = 0.008). Moreover, both intracellular and extracellular HDGF were proved to promote the proliferation, invasion, and angiogenesis of IHCC cell lines. In conclusion, HDGF was identified as an independent prognostic biomarker in IHCC. HDGF can promote IHCC cells progression, including proliferation, invasion, and angiogenesis, indicating HDGF could become a new promising and potential drug target of IHCC.

Keywords

Hepatoma-derived growth factor Intrahepatic cholangiocarcinoma Prognosis Tumor progression Angiogenesis 

Notes

Acknowledgment

This study is funded by the Outstanding Young Scientist Award Fund supported by Shandong Province (no. BS2012YY021).

Conflicts of interest

None

References

  1. 1.
    Nakamura H, Izumoto Y, Kambe H, Kuroda T, Mori T, Kawamura K, et al. Molecular cloning of complementary DNA for a novel human hepatoma-derived growth factor. Its homology with high mobility group-1 protein. J Biol Chem. 1994;269:25143–9.PubMedGoogle Scholar
  2. 2.
    Enomoto H, Yoshida K, Kishima Y, Kinoshita T, Yamamoto M, Everett AD, et al. Hepatoma-derived growth factor is highly expressed in developing liver and promotes fetal hepatocyte proliferation. Hepatology. 2002;36:1519–27.CrossRefPubMedGoogle Scholar
  3. 3.
    Chang KC, Tai MH, Lin JW, Wang CC, Huang CC, Hung CH, et al. Hepatoma-derived growth factor is a novel prognostic factor for gastrointestinal stromal tumors. Int J Cancer J Int Cancer. 2007;121:1059–65.CrossRefGoogle Scholar
  4. 4.
    Uyama H, Tomita Y, Nakamura H, Nakamori S, Zhang B, Hoshida Y, et al. Hepatoma-derived growth factor is a novel prognostic factor for patients with pancreatic cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:6043–8.CrossRefGoogle Scholar
  5. 5.
    Yamamoto S, Tomita Y, Hoshida Y, Takiguchi S, Fujiwara Y, Yasuda T, et al. Expression of hepatoma-derived growth factor is correlated with lymph node metastasis and prognosis of gastric carcinoma. Clin Cancer Res: An Off J Am Assoc Cancer Res. 2006;12:117–22.CrossRefGoogle Scholar
  6. 6.
    Hu TH, Huang CC, Liu LF, Lin PR, Liu SY, Chang HW, et al. Expression of hepatoma-derived growth factor in hepatocellular carcinoma. Cancer. 2003;98:1444–56.CrossRefPubMedGoogle Scholar
  7. 7.
    Ren H, Tang X, Lee JJ, Feng L, Everett AD, Hong WK, et al. Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small-cell lung cancer. J Clin Oncol: Off J Am Soc Clin Oncol. 2004;22:3230–7.CrossRefGoogle Scholar
  8. 8.
    Abouzied MM, El-Tahir HM, Prenner L, Haberlein H, Gieselmann V, Franken S. Hepatoma-derived growth factor. Significance of amino acid residues 81–100 in cell surface interaction and proliferative activity. J Biol Chem. 2005;280:10945–54.CrossRefPubMedGoogle Scholar
  9. 9.
    Okuda Y, Nakamura H, Yoshida K, Enomoto H, Uyama H, Hirotani T, et al. Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor. Cancer Sci. 2003;94:1034–41.CrossRefPubMedGoogle Scholar
  10. 10.
    Everett AD, Narron JV, Stoops T, Nakamura H, Tucker A. Hepatoma-derived growth factor is a pulmonary endothelial cell-expressed angiogenic factor. Am J Physiol Lung Cell Mol Physiol. 2004;286:L1194–201.CrossRefPubMedGoogle Scholar
  11. 11.
    Kishima Y, Yamamoto H, Izumoto Y, Yoshida K, Enomoto H, Yamamoto M, et al. Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus by nuclear localization signals. J Biol Chem. 2002;277:10315–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol. 2012;57:69–76.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sempoux C, Jibara G, Ward SC, Fan C, Qin L, Roayaie S, et al. Intrahepatic cholangiocarcinoma: new insights in pathology. Sem Liver Dis. 2011;31:49–60.CrossRefGoogle Scholar
  14. 14.
    Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Patel T. Cholangiocarcinoma—controversies and challenges. Nat Rev Gastroenterol Hepatol. 2011;8:189–200.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Xu YF, Yang XQ, Lu XF, Guo S, Liu Y, Iqbal M, et al. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma. Biochem Biophys Res Commun. 2014;446:54–60.CrossRefPubMedGoogle Scholar
  17. 17.
    Rimm DL, Camp RL, Charette LA, Costa J, Olsen DA, Reiss M. Tissue microarray: a new technology for amplification of tissue resources. Cancer J. 2001;7:24–31.PubMedGoogle Scholar
  18. 18.
    Liu YF, Zhao R, Guo S, Wang XQ, Lian PL, Chen YG, et al. Expression and clinical significance of hepatoma-derived growth factor as a prognostic factor in human hilar cholangiocarcinoma. Ann Surg Oncol. 2011;18:872–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Gasparini G, Weidner N, Bevilacqua P, Maluta S, Dalla Palma P, Caffo O, et al. Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol. 1994;12:454–66.CrossRefGoogle Scholar
  20. 20.
    Erbersdobler A, Isbarn H, Dix K, Steiner I, Schlomm T, Mirlacher M, et al. Prognostic value of microvessel density in prostate cancer: a tissue microarray study. World J Urol. 2010;28:687–92.CrossRefPubMedGoogle Scholar
  21. 21.
    Thelen A, Scholz A, Weichert W, Wiedenmann B, Neuhaus P, Gessner R, et al. Tumor-associated angiogenesis and lymphangiogenesis correlate with progression of intrahepatic cholangiocarcinoma. Am J Gastroenterol. 2010;105:1123–32.CrossRefPubMedGoogle Scholar
  22. 22.
    Guo Z, He Y, Wang S, Zhang A, Zhao P, Gao C, et al. Various effects of hepatoma-derived growth factor on cell growth, migration and invasion of breast cancer and prostate cancer cells. Oncol Rep. 2011;26:511–7.PubMedGoogle Scholar
  23. 23.
    Kolokythas A, Cox DP, Dekker N, Schmidt BL. Nerve growth factor and tyrosine kinase a receptor in oral squamous cell carcinoma: is there an association with perineural invasion? J Oral Maxillofac Surg: Off J Am Assoc Oral Maxillofac Surg. 2010;68:1290–5.CrossRefGoogle Scholar
  24. 24.
    Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25.CrossRefPubMedGoogle Scholar
  25. 25.
    Yang Y, Li H, Zhang F, Shi H, Zhen T, Dai S, et al. Clinical and biological significance of hepatoma-derived growth factor in Ewing’s sarcoma. J Pathol. 2013;231:323–34.CrossRefPubMedGoogle Scholar
  26. 26.
    Chen SC, Kung ML, Hu TH, Chen HY, Wu JC, Kuo HM, et al. Hepatoma-derived growth factor regulates breast cancer cell invasion by modulating epithelial–mesenchymal transition. J Pathol. 2012;228:158–69.CrossRefPubMedGoogle Scholar
  27. 27.
    Everett AD, Lobe DR, Matsumura ME, Nakamura H, McNamara CA. Hepatoma-derived growth factor stimulates smooth muscle cell growth and is expressed in vascular development. J Clin Investig. 2000;105:567–75.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Everett AD, Bushweller J. Hepatoma derived growth factor is a nuclear targeted mitogen. Curr Drug Targets. 2003;4:367–71.CrossRefPubMedGoogle Scholar
  29. 29.
    Everett AD, Stoops T, McNamara CA. Nuclear targeting is required for hepatoma-derived growth factor-stimulated mitogenesis in vascular smooth muscle cells. J Biol Chem. 2001;276:37564–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Ooi BN, Mukhopadhyay A, Masilamani J, Do DV, Lim CP, Cao XM, et al. Hepatoma-derived growth factor and its role in keloid pathogenesis. J Cell Mol Med. 2010;14:1328–37.CrossRefPubMedGoogle Scholar
  31. 31.
    Tsang TY, Tang WY, Tsang WP, Co NN, Kong SK, Kwok TT. Mechanistic study on growth suppression and apoptosis induction by targeting hepatoma-derived growth factor in human hepatocellular carcinoma HepG2 cells. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol. 2009;24:253–62.CrossRefGoogle Scholar
  32. 32.
    Tsai HE, Liu GS, Kung ML, Liu LF, Wu JC, Tang CH, et al. Downregulation of hepatoma-derived growth factor contributes to retarded lung metastasis via inhibition of epithelial-mesenchymal transition by systemic POMC gene delivery in melanoma. Mol Cancer Ther. 2013;12:1016–25.CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang J, Ren H, Yuan P, Lang W, Zhang L, Mao L. Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells. Cancer Res. 2006;66:18–23.CrossRefPubMedGoogle Scholar
  34. 34.
    Ren H, Chu Z, Mao L. Antibodies targeting hepatoma-derived growth factor as a novel strategy in treating lung cancer. Mol Cancer Ther. 2009;8:1106–12.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Thirant C, Galan-Moya EM, Dubois LG, Pinte S, Chafey P, Broussard C, et al. Differential proteomic analysis of human glioblastoma and neural stem cells reveals hdgf as a novel angiogenic secreted factor. Stem Cells. 2012;30:845–53.CrossRefPubMedGoogle Scholar
  36. 36.
    Hsu SS, Chen CH, Liu GS, Tai MH, Wang JS, Wu JC, et al. Tumorigenesis and prognostic role of hepatoma-derived growth factor in human gliomas. J Neuro-Oncol. 2012;107:101–9.CrossRefGoogle Scholar
  37. 37.
    von Heijne G. A new method for predicting signal sequence cleavage sites. Nucleic Acids Res. 1986;14:4683–90.CrossRefGoogle Scholar
  38. 38.
    Nakamura H, Kambe H, Egawa T, Kimura Y, Ito H, Hayashi E, et al. Partial purification and characterization of human hepatoma-derived growth factor. Clin Chim Acta Int J Clin Chem. 1989;183:273–84.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Sen Guo
    • 1
    • 5
  • Hong-da Liu
    • 1
  • Yan-feng Liu
    • 1
  • Lei Liu
    • 2
  • Qiang Sun
    • 3
  • Xi-jun Cui
    • 4
  1. 1.Department of General SurgeryQilu Hospital of Shandong UniversityJinanChina
  2. 2.Department of General SurgeryPeople Hospital of HantingWeifang CityChina
  3. 3.Department of SurgeryBinhai Branch of Weifang Hospital of Traditional Chinese MedicineWeifang CityChina
  4. 4.Department of General SurgeryWendeng Central HospitalWeihai CityChina
  5. 5.Department of Hepatobiliary SurgeryQilu Hospital of Shandong UniversityJinanChina

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