The interplay of matrix metalloproteinase-8, transforming growth factor-β1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

Br J Cancer. 2017 Sep 26;117(7):1007-1016. doi: 10.1038/bjc.2017.249. Epub 2017 Aug 3.

Abstract

Background: Matrix metalloproteinase-8 (MMP-8) has oncosuppressive properties in various cancers. We attempted to assess MMP-8 function in oral tongue squamous cell carcinoma (OTSCC).

Methods: MMP-8 overexpressing OTSCC cells were used to study the effect of MMP-8 on proliferation, apoptosis, migration, invasion and gene and protein expression. Moreover, MMP-8 functions were assessed in the orthotopic mouse tongue cancer model and by immunohistochemistry in patient samples.

Results: MMP-8 reduced the invasion and migration of OTSCC cells and decreased the expression of MMP-1, cathepsin-K and vascular endothelial growth factor-C (VEGF-C). VEGF-C was induced by transforming growth factor-β1 (TGF-β1) in control cells, but not in MMP-8 overexpressing cells. In human OTSCC samples, low MMP-8 in combination with high VEGF-C was an independent predictor of poor cancer-specific survival. TGF-β1 treatment also restored the migration of MMP-8 overexpressing cells to the level of control cells. In mouse tongue cancer, MMP-8 did not inhibit metastasis, possibly because it was eliminated in the peripheral carcinoma cells.

Conclusions: The suppressive effects of MMP-8 in OTSCC may be mediated through interference of TGF-β1 and VEGF-C function and altered proteinase expression. Together, low MMP-8 and high VEGF-C expression have strong independent prognostic value in OTSCC.

MeSH terms

  • Aged
  • Animals
  • Apoptosis
  • Carcinoma, Squamous Cell / chemistry
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / secondary
  • Cathepsin K / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 8 / analysis
  • Matrix Metalloproteinase 8 / genetics*
  • Matrix Metalloproteinase 8 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Neoplasm Transplantation
  • Prognosis
  • Survival Rate
  • Tongue Neoplasms / chemistry
  • Tongue Neoplasms / genetics
  • Tongue Neoplasms / metabolism*
  • Tongue Neoplasms / pathology
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Vascular Endothelial Growth Factor C / metabolism*

Substances

  • Transforming Growth Factor beta1
  • Vascular Endothelial Growth Factor C
  • Cathepsin K
  • Matrix Metalloproteinase 8
  • Matrix Metalloproteinase 1