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

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.

Matrix metalloproteinase 9 inhibits the motility of highly aggressive HSC-3 oral squamous cell carcinoma cells

“…Importantly, M2 macrophage is the phenotype displayed by most tumour-associated macrophages able to induce cancer growth [36]. We have also demonstrated that MMP8overexpressing HSC-3 cells, with significantly decreased cell invasion and migration, have increased MMP9 expression [12]. Here, we further showed that arrHSC-3 cells, also revealed to have reduced motility [19], had elevated MMP9 expression levels and a concomitant reduction in the amount of MMP2.…”

“…Because of the diversity of the effects and functions of MMP9 reported in vitro, it would be highly important to evaluate whether the upregulated MMP9 in vivo has a true pathogenic effect or whether the upregulation is actually caused by the disease. The upregulation of MMP9 may also be a protective response of the host against the tumour [47], as in the case of MMP8 [12,55]. MMPs in vivo may play both pro-and antitumorigenic roles, depending on the nature of the cancer.…”

“…Medium with 1% FBS was added after 10 h and the total RNA was extracted using RNEasy Mini Kit (Qiagen) according to the manufacturer's instructions. Microarray was performed and analysed by Affymetrix GeneChip Human Genome U133 Plus 2.0 according to the Affymetrix GeneChip Expression Analysis Technical Manual's instructions using 1 μg of total RNA as template (described in detail previously [12]). The arrays were scanned on a GeneChip Scanner 3000 and DAVID 6.7 was used for Gene Ontology analyses [27].…”

“…Recently, we have reported increased MMP9 expression in HSC-3 clone overexpressing MMP8 with decreased migration and invasion [12]. Additionally, although anti-MMP2 and -9 peptides inhibit tongue carcinoma growth [13,14] and angiogenesis [13], they do not prevent the spread of carcinoma cells in nude mice [14].…”

Micro‐RNAs as critical regulators of matrix metalloproteinases in cancer

“…MMP-8 is a collagenase-2 that has oncosuppressive properties in different cancers. 47 It was already suspected that MMP-8 is produced at high levels by polymorphonuclear leukocytes (PMN) cells in the bone marrow and that the movement of MMP-8 is dependent on presence of the enzyme from PMN cells by degranulation. Nonetheless, recent studies have reported the presence of MMP-8 in mesenchyme-determined, non-PMN lineage cell lines, including human cartilage chondrocytes, synovial fibroblasts, and endothelial cells.…”