Tumor Biology

, Volume 35, Issue 11, pp 11005–11011 | Cite as

RETRACTED ARTICLE: Inhibition of fibroblast growth factor receptor signaling impairs metastasis of hepatocellular carcinoma

Research Article

Abstract

The molecular mechanism underlying metastasis of hepatocellular carcinoma (HCC) remains elusive. Here, we showed that matrix metalloproteinase (MMP) 7 and MMP26 levels are significantly higher in the resected HCC than in the adjacent healthy hepatic cells from the patients. Moreover, a strong correlation of the levels of MMP7 or MMP26 with the phosphorylated fibroblast growth factor receptor 2 (FGFR2) was detected. To prove a causal link between the activation of FGFR signaling pathway and expression of MMP7 and MMP26, we used two human HCC lines, HepG2 and HuH-7, to study the underlying molecular basis. We found that FGF1-induced FGFR2 phosphorylation in either line resulted in significant activation of MMP7 and MMP26 and consequently an increase in cancer invasiveness. Inhibition of FGFR2 phosphorylation in HCC abolished FGF1-stimulated MMP7 and MMP26 expression, suggesting that activation of the FGFR signaling pathway in HCC may promote cancer metastasis by inducing MMP7 and MMP26 expression. To define the signal transduction cascades downstream of FGFR2 activation for MMP7 and MMP26 activation, we applied specific inhibitors for phosphatidylinositol-3 kinase (PI3K), extracellular signal-related kinase/mitogen-activated protein kinase (ERK/MAPK), and Jun N-terminal kinase (JNK), respectively, to the FGF1-stimulated HCC cells. We found that only inhibition of JNK significantly decreased the activation of MMP26 in response to FGF1 stimulation, and only inhibition of PI3K significantly decreased the activation of MMP7 in response to FGF1 stimulation, suggesting that the activation of the FGFR2 signaling may activate PI3K to activate MMP7 and activate JNK to activate MMP26, in HCC. Our study thus highlights the FGFR2 signaling pathway and MMP7 and MMP26 as novel therapeutic targets for HCC.

Keywords

Fibroblast growth factor receptor 2 Hepatocellular carcinoma MMP7 MMP26 HepG2 HuH-7 ERK/MAPK PI3K JNK 

Notes

Conflicts of interest

None

References

  1. 1.
    Wang L, Yao M, Dong Z, Zhang Y, Yao D. Circulating specific biomarkers in diagnosis of hepatocellular carcinoma and its metastasis monitoring. Tumour Biol. 2014;35:9–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Wang H, Chen L. Tumor microenviroment and hepatocellular carcinoma metastasis. J Gastroenterol Hepatol. 2013;28 Suppl 1:43–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Han MS, Moon KS, Lee KH, Cho SB, Lim SH, Jang WY, et al. Brain metastasis from hepatocellular carcinoma: the role of surgery as a prognostic factor. BMC Cancer. 2013;13:567.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Takaishi H, Kimura T, Dalal S, Okada Y, D’Armiento J. Joint diseases and matrix metalloproteinases: a role for mmp-13. Curr Pharm Biotechnol. 2008;9:47–54.CrossRefPubMedGoogle Scholar
  5. 5.
    Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (mmp-1, mmp-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 2002;4:157–64.CrossRefPubMedGoogle Scholar
  6. 6.
    Balbin M, Pendas AM, Uria JA, Jimenez MG, Freije JP, Lopez-Otin C. Expression and regulation of collagenase-3 (mmp-13) in human malignant tumors. APMIS. 1999;107:45–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Tanimoto H, Underwood LJ, Shigemasa K, Parmley TH, Wang Y, Yan Y, et al. The matrix metalloprotease pump-1 (mmp-7, matrilysin): a candidate marker/target for ovarian cancer detection and treatment. Tumour Biol. 1999;20:88–98.CrossRefPubMedGoogle Scholar
  8. 8.
    Koskensalo S, Mrena J, Wiksten JP, Nordling S, Kokkola A, Hagstrom J, et al. Mmp-7 overexpression is an independent prognostic marker in gastric cancer. Tumour Biol. 2010;31:149–55.CrossRefPubMedGoogle Scholar
  9. 9.
    Koskensalo S, Louhimo J, Nordling S, Hagstrom J, Haglund C. Mmp-7 as a prognostic marker in colorectal cancer. Tumour Biol. 2011;32:259–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Ii M, Yamamoto H, Adachi Y, Maruyama Y, Shinomura Y. Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med (Maywood). 2006;231:20–7.Google Scholar
  11. 11.
    Liu G, Jiang C, Li D, Wang R, Wang W. Mirna-34a inhibits egfr-signaling-dependent mmp7 activation in gastric cancer. Tumour Biol. 2014.Google Scholar
  12. 12.
    Zhang Y, Zhao H, Wang Y, Lin Y, Tan Y, Fang X, et al. Non-small cell lung cancer invasion and metastasis promoted by mmp-26. Mol Med Rep. 2011;4:1201–9.PubMedGoogle Scholar
  13. 13.
    Li D. Peaking of mmp-26 and timp-4 marks invasive transition in prostate cancer. Cell Res. 2006;16:741.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamamoto H, Vinitketkumnuen A, Adachi Y, Taniguchi H, Hirata T, Miyamoto N, et al. Association of matrilysin-2 (mmp-26) expression with tumor progression and activation of mmp-9 in esophageal squamous cell carcinoma. Carcinogenesis. 2004;25:2353–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Friesel R, Maciag T. Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling. Thromb Haemost. 1999;82:748–54.PubMedGoogle Scholar
  16. 16.
    Jaye M, Schlessinger J, Dionne CA. Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim Biophys Acta. 1992;1135:185–99.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang X, Cao X. Regulation of metastasis of pediatric multiple myeloma by mmp13. Tumour Biol. 2014.Google Scholar
  18. 18.
    Fujimoto J, Hori M, Ichigo S, Tamaya T. Expressions of the fibroblast growth factor family (fgf-1, −2 and −4) mrna in endometrial cancers. Tumour Biol. 1996;17:226–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Soundararajan P, Fawcett JP, Rafuse VF. Guidance of postural motoneurons requires mapk/erk signaling downstream of fibroblast growth factor receptor 1. J Neurosci. 2010;30:6595–606.CrossRefPubMedGoogle Scholar
  20. 20.
    Kuslak SL, Marker PC. Fibroblast growth factor receptor signaling through mek-erk is required for prostate bud induction. Differentiation. 2007;75:638–51.CrossRefPubMedGoogle Scholar
  21. 21.
    Williamson AJ, Dibling BC, Boyne JR, Selby P, Burchill SA. Basic fibroblast growth factor-induced cell death is effected through sustained activation of p38mapk and up-regulation of the death receptor p75ntr. J Biol Chem. 2004;279:47912–28.CrossRefPubMedGoogle Scholar
  22. 22.
    Kan M, Wu X, Wang F, McKeehan WL. Specificity for fibroblast growth factors determined by heparan sulfate in a binary complex with the receptor kinase. J Biol Chem. 1999;274:15947–52.CrossRefPubMedGoogle Scholar
  23. 23.
    Fletcher MN, Castro MA, Wang X, de Santiago I, O’Reilly M, Chin SF, et al. Master regulators of fgfr2 signalling and breast cancer risk. Nat Commun. 2013;4:2464.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Liao RG, Jung J, Tchaicha J, Wilkerson MD, Sivachenko A, Beauchamp EM, et al. Inhibitor-sensitive fgfr2 and fgfr3 mutations in lung squamous cell carcinoma. Cancer Res. 2013;73:5195–205.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kang M, Choi S, Jeong SJ, Lee SA, Kwak TK, Kim H, et al. Cross-talk between tgfbeta1 and egfr signalling pathways induces tm4sf5 expression and epithelial-mesenchymal transition. Biochem J. 2012;443:691–700.CrossRefPubMedGoogle Scholar
  26. 26.
    Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of smad7. Proc Natl Acad Sci U S A. 2014;111:E1211–20.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Xu Y, Xia W, Baker D, Zhou J, Cha HC, Voorhees JJ, et al. Receptor-type protein tyrosine phosphatase beta (rptp-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (hgfr/met) function. J Biol Chem. 2011;286:15980–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of Radiologythe First Hospital of China Medical UniversityShenyangChina

Personalised recommendations