This study revealed an interesting finding that MMP-1 and MMP-13 protein expression in the BRAF V600 mutated melanomas were significantly lower than in the BRAF V600 wild type (P < 0.05).
Our findings highlight the role of BRAF(V600E) in activating the stroma and suggest a mechanistic link between BRAF(V600E) and MMP-1 in mediating melanoma progression and in activating adjacent fibroblasts in the tumour microenvironment.
Together, these studies mechanistically show a previously unrecognized interplay between ERK1/2, TWIST1, and MMP-1 that is likely significant in the progression of melanoma toward metastasis.
As primary tumor thickness and ulceration status are two important indicators of tumor progression and have significant associations with melanoma prognosis, our results suggested that these promoter SNPs in MMP1 might have potential effects on melanoma progression and prognosis by influencing related clinical factors.
These results show, for the first time, that targeted inhibition of MMP-1, a single effector of the Raf/MEK/ERK signaling cascade, prevents the progression of melanoma from a primary to metastatic tumor and, as such, may represent a useful therapeutic tool in controlling this disease.
In this study, we assessed the functional effects of these polymorphisms on MMP1 gene promoter activity in cell lines of melanoma (A2058 and A375), breast cancer (MCF7 and MDA-MB-231), lung cancer (A549 and H69), and colorectal cancer (HT-29, SW-620) by comparing the promoter strengths of 10 most common haplotypes deriving from these polymorphisms.
Thus, these results suggest that MMP-1 produced from melanoma cells would play a role in tumor progression by both degrading matrix proteins and generating active growth factors such as TGF-beta in vivo.
Furthermore, activation of this pathway in transformed melanoma cells (A2058) results in increased expression and activity of MMP-1, MMP-2 and MMP-9, as well as increased invasion using in vitro invasion assays.
Taken together, our results indicate an essential role for soluble factors, mainly IL-1alpha and bFGF, in the stimulation of dermal fibroblasts by human melanoma cells to secrete MMP-1.
Basic fibroblast growth factor (bFGF) was detected as an important factor responsible for the enhanced expression of MMP-1 by fibroblasts after stimulation with melanoma cell conditioned medium.
Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease.
We report here the development of quantitative methods for assessing allelic loss at the MMP-1 locus, and demonstrate that 83% of the metastatic melanomas with loss of heterozygosity at this locus retained the 2G allele.
Of particular interest is a single nucleotide polymorphism in the MMP-1 promoter that increases the transcription of this gene and that is associated with melanoma and with ovarian and endometrial cancers.
In the present study we analysed the role of type I collagenase (MMP-1) in melanoma invasion using MIM cells in which the constitutive expression of MMP-1 was suppressed by stable transfection with a plasmid vector expressing a 777 bp antisense fragment of MMP-1 genomic DNA.
A full-length complementary DNA (cDNA) for interstitial collagenase was isolated from an A2058 melanoma cDNA library using the pCD-X Okayama-Berg vector.