Digestive Diseases and Sciences

, Volume 58, Issue 7, pp 1916–1922 | Cite as

Expression of Fibroblast Growth Factor 19 Is Associated with Recurrence and Poor Prognosis of Hepatocellular Carcinoma

  • Jiyeon Hyeon
  • Soomin Ahn
  • Jae Jun Lee
  • Dae Hyun Song
  • Cheol-Keun Park
Original Article



Fibroblast growth factor 19 (FGF19)-mediated activation of mitogen-activated protein kinase and the β-catenin pathway may be involved in the development and progression of hepatocellular carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients.


By immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6 months.


FGF19 protein expression was observed in 135 (48.0 %) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size (P < 0.001), and higher BCLC stage (P = 0.001). FGF19 expression was correlated with the early recurrence (P < 0.001), but not with the late recurrence (P = 0.582). FGF19 expression (P = 0.002), viral etiology (P = 0.028), and intrahepatic metastasis (P < 0.001) were independent predictors of early recurrence. Multivariate analyses of survival revealed that FGF19 expression (P < 0.001), intrahepatic metastasis (P < 0.001), and liver cirrhosis (P = 0.019) were independent predictors of shorter disease-free survival. FGF19 expression (P = 0.005), larger tumor size (P = 0.038), major portal vein invasion (P = 0.048), intrahepatic metastasis (P < 0.001), lower albumin level (P = 0.024), and liver cirrhosis (P = 0.031) were independent predictors of shorter disease-specific survival.


FGF19 protein expression might be an effective predictor of early recurrence and a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy, indicating that FGF19 might be a potential preventive target in hepatocellular carcinoma patients.


FGF19 Hepatocellular carcinoma Recurrence Survival 


  1. 1.
    Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181–200.PubMedCrossRefGoogle Scholar
  2. 2.
    Poon RT. Prevention of recurrence after resection of hepatocellular carcinoma: a daunting challenge. Hepatology. 2011;54:757–759.PubMedCrossRefGoogle Scholar
  3. 3.
    Ho MC, Lin JJ, Chen CN, et al. A gene expression profile for vascular invasion can predict the recurrence after resection of hepatocellular carcinoma: a microarray approach. Ann Surg Oncol. 2006;13:1474–1484.PubMedCrossRefGoogle Scholar
  4. 4.
    Qin LX, Tang ZY. Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature. J Cancer Res Clin Oncol. 2004;130:497–513.PubMedCrossRefGoogle Scholar
  5. 5.
    Ornitz DM, Itoh N. Fibroblast growth factors. Genome Biol. 2001;2:reviews3005.1–12.CrossRefGoogle Scholar
  6. 6.
    Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer. 2000;7:165–197.PubMedCrossRefGoogle Scholar
  7. 7.
    Kurosu H, Choi M, Ogawa Y, et al. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem. 2007;282:26687–26695.PubMedCrossRefGoogle Scholar
  8. 8.
    Pai R, Dunlap D, Qing J, et al. Inhibition of fibroblast growth factor 19 reduces tumor growth by modulating β-catenin signaling. Cancer Res. 2008;68:5086–5095.PubMedCrossRefGoogle Scholar
  9. 9.
    French DM, Lin BC, Wang M, et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. PLoS One. 2012;7:e36713.PubMedCrossRefGoogle Scholar
  10. 10.
    Nicholes K, Guillet S, Tomlinson E, et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol. 2002;160:2295–2307.PubMedCrossRefGoogle Scholar
  11. 11.
    Desnoyers LR, Pai R. Ferrando RE, et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene. 2008;27:85–97.PubMedCrossRefGoogle Scholar
  12. 12.
    Sawey ET, Chanrion M, Cai C, et al. Identification of therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell. 2011;19:347–358.PubMedCrossRefGoogle Scholar
  13. 13.
    Miura S, Mitsuhashi N, Shimizu H, et al. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer. 2012;12:56.PubMedCrossRefGoogle Scholar
  14. 14.
    Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.PubMedCrossRefGoogle Scholar
  15. 15.
    Kumada T, Nakano S, Takeda I, et al. Patterns of recurrence after initial treatment in patients with small hepatocellular carcinoma. Hepatology. 1997;25:87–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A III. AJCC cancer staging manual. 7th ed. Chicago, IL: Springer; 2010.Google Scholar
  17. 17.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–338.PubMedCrossRefGoogle Scholar
  18. 18.
    Shimada M, Hamatsu T, Yamashita Y, et al. Characteristics of multicentric hepatocellular carcinomas: comparison with intrahepatic metastasis. World J Surg. 2001;25:991–995.PubMedCrossRefGoogle Scholar
  19. 19.
    Imamura H, Matsuyama Y, Tanaka T, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–207.PubMedCrossRefGoogle Scholar
  20. 20.
    Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359:1995–2004.PubMedCrossRefGoogle Scholar
  21. 21.
    Kim SH, Ahn S, Park CK. Smad3 and its phosphoisoforms are prognostic predictors of hepatocellular carcinoma after curative hepatectomy. Hepatobiliary Pancreat Dis Int. 2012;11:51–59.PubMedCrossRefGoogle Scholar
  22. 22.
    Katzmann DJ, Odorizzi G, Emr SD. Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol. 2002;3:893–905.PubMedCrossRefGoogle Scholar
  23. 23.
    Dobrowolski R, De Robertis EM. Endocytotic control of growth factor signalling: multivesicular bodies as signalling organelles. Nat Rev Mol Cell Biol. 2011;13:53–60.PubMedGoogle Scholar
  24. 24.
    Polakis P. Wnt signaling and cancer. Genes Dev. 2000;14:1837–1851.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Jiyeon Hyeon
    • 1
  • Soomin Ahn
    • 1
  • Jae Jun Lee
    • 1
  • Dae Hyun Song
    • 1
  • Cheol-Keun Park
    • 1
  1. 1.Department of Pathology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea

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