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
Åström, Pirjo; Juurikka, Krista; Hadler-Olsen, Elin S; Svineng, Gunbjørg; Cervigne, Nilva K; Coletta, Ricardo D; Risteli, Juha; Kauppila, Joonas H; Skarp, Sini; Kuttner, Samuel; Oteiza, Ana; Sutinen, Meeri; Salo, Tuula (2017-08-03)
Åström, P., Juurikka, K., Hadler-Olsen, E., Svineng, G., Cervigne, N., Coletta, R., Risteli, J., Kauppila, J., Skarp, S., Kuttner, S., Oteiza, A., Sutinen, M., Salo, T. (2017) 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. British Journal of Cancer, 117 (7), 1007-1016. doi:10.1038/bjc.2017.249
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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.
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