The interplay of matrix metalloproteinase-8, transforming growth factor-[beta]1 and vascular endothelial growth factor-C cooperatively contributes to the aggressiveness of oral tongue squamous cell carcinoma

• Published in: British journal of cancer Vol. 117; no. 7; p. 1007
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 26.09.2017
• Subjects: Apoptosis; Cancer; Cell proliferation; Immunohistochemistry; Interstitial collagenase; Matrix metalloproteinase; Metalloproteinase; Metastases; Neutrophil collagenase; Oral cancer; Proteinase; Rodents; Squamous cell carcinoma; Tongue; Transforming growth factor-b1; Vascular endothelial growth factor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.249

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.