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
AuthorÅström, Pirjo; Juurikka, Krista; Hadler-Olsen, Elin Synnøve; Svineng, Gunbjørg; Cervigne, Nilva K.; Coletta, Ricardo D.; Risteli, Juha; Kauppila, Joonas H.; Skarp, Sini; Kuttner, Samuel; Oteiza, Ana; Sutinen, Meeri; Salo, Tuula
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-b1 (TGF-b1) 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-b1 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-b1 and VEGF-C function and altered proteinase expression. Together, low MMP-8 and high VEGF-C expression have strong independent prognostic value in OTSCC.