Tumor Biology

, Volume 35, Issue 9, pp 9381–9386 | Cite as

RETRACTED ARTICLE: PLGF inhibition impairs metastasis of larynx carcinoma through MMP3 downregulation

Research Article

Abstract

Cancer neovascularization plays a key role in the metastasis of larynx carcinoma. However, the molecular mechanism for the neovascularization control in larynx carcinoma is poorly understood. Since placental growth factor (PLGF) has been reported to be involved in pathological angiogenesis, and since matrix metalloproteinases (MMPs) are essential for extracellular matrix degradation during neovascularization, here we were prompted to examine whether PLGF and MMPs may play a coordinate role in the metastasis of larynx carcinoma. Our data showed that the expression of PLGF and MMP3 strongly correlated in the larynx carcinoma in the patients, and significant higher levels of PLGF and MMP3 were detected in the larynx carcinoma from the patients with metastasis of the primary cancer. Thus, we used a human larynx carcinoma cell line, Hep-2, to examine whether expression of PLGF and MMP3 may affect each other. We found that overexpression of PLGF in Hep-2 cells increased expression of MMP3, while inhibition of PLGF in Hep-2 cells decreased expression of MMP3. However, neither overexpression, nor inhibition of MMP3 in Hep-2 cells affected the expression level of PLGF. These data suggest that PLGF may function upstream of MMP3 in larynx carcinoma cells. We then analyzed how PLGF affected MMP3. Application of a specific ERK1/2 inhibitor to PLGF-overexpressing Hep-2 cells substantially abolished the effect of PLGF on MMP3 activation, suggesting that PLGF may increase expression of MMP3 via ERK/MAPK signaling pathway. Since anti-PLGF was recently applied in clinical trials to inhibit cancer-related angiogenesis, here our data further demonstrate that inhibition of cancer neovascularization by anti-PLGF is mediated not only by direct effect on endothelial growth and capillary permeability, but also by indirect effect via MMP3 on the extracellular matrix degradation in larynx carcinoma.

Keywords

Placental growth factor Matrix metalloproteinases 3 ERK/MAPK signaling pathway Larynx carcinoma Metastasis 

Notes

Conflicts of interest

None

References

  1. 1.
    Zhao X, Li X, Yuan H. MicroRNAs in gastric cancer invasion and metastasis. Front Biosci. 2013;18:803–10.CrossRefGoogle Scholar
  2. 2.
    Kim JG. Molecular targeted therapy for advanced gastric cancer. Korean J Intern Med. 2013;28:149–55.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ilson DH. Angiogenesis in gastric cancer: hitting the target? Lancet. 2014;383:4–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Scartozzi M, Giampieri R, Loretelli C, Bittoni A, Mandolesi A, Faloppi L, et al. Tumor angiogenesis genotyping and efficacy of first-line chemotherapy in metastatic gastric cancer patients. Pharmacogenomics. 2013;14:1991–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Dufour A, Overall CM. Missing the target: matrix metalloproteinase antitargets in inflammation and cancer. Trends Pharmacol Sci. 2013;34:233–42.CrossRefPubMedGoogle Scholar
  6. 6.
    Ferrara N. Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol. 2009;29:789–91.CrossRefPubMedGoogle Scholar
  7. 7.
    Xiao X, Prasadan K, Guo P, El-Gohary Y, Fischbach S, Wiersch J, et al. Pancreatic duct cells as a source of VEGF in mice. Diabetologia. 2014;57:991–1000.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Xiao X, Guo P, Chen Z, El-Gohary Y, Wiersch J, Gaffar I, et al. Hypoglycemia reduces vascular endothelial growth factor a production by pancreatic beta cells as a regulator of beta cell mass. J Biol Chem. 2013;288:8636–46.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med. 2001;7:575–83.CrossRefPubMedGoogle Scholar
  10. 10.
    Eriksson A, Cao R, Pawliuk R, Berg SM, Tsang M, Zhou D, et al. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PLGF-1/VEGF heterodimers. Cancer Cell. 2002;1:99–108.CrossRefPubMedGoogle Scholar
  11. 11.
    Davidson B, Reich R, Risberg B, Nesland JM. The biological role and regulation of matrix metalloproteinases (mmp) in cancer. Arkh Patol. 2002;64:47–53.PubMedGoogle Scholar
  12. 12.
    Rhee JS, Coussens LM. Recking mmp function: implications for cancer development. Trends Cell Biol. 2002;12:209–11.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhang C, Li C, Zhu M, Zhang Q, Xie Z, Niu G, et al. Meta-analysis of mmp2, mmp3, and mmp9 promoter polymorphisms and head and neck cancer risk. PLoS ONE. 2013;8:e62023.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mendes O, Kim HT, Stoica G. Expression of mmp2, mmp9 and mmp3 in breast cancer brain metastasis in a rat model. Clin Exp Metastasis. 2005;22:237–46.CrossRefPubMedGoogle Scholar
  15. 15.
    Biggs 3rd WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci U S A. 1999;96:7421–6.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bagri A, Kouros-Mehr H, Leong KG, Plowman GD. Use of anti-VEGF adjuvant therapy in cancer: challenges and rationale. Trends Mol Med. 2010;16:122–32.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Otorhinolaryngology Department, Zhongshan HospitalFu Dan UniversityShangHaiChina

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