Association of a single nucleotide polymorphism in the matrix metalloproteinase‐1 promoter with glioblastoma

Abstract

A key feature in the malignant behavior of glioblastoma is the tendency to invade host brain tissue surrounding the primary tumor site. Several members of the matrix metalloproteinase family are thought to contribute to this invasive capacity. A single nucleotide polymorphism has been described in the matrix metalloproteinase-1 (MMP-1) promoter that consists of either the presence or absence of a guanine nucleotide at position 21607. The presence of the guanine base creates a functional binding site for members of the ETS family of transcription factors and has been shown to increase MMP-1 transcription. The purpose of our study was to characterize this polymorphism in human glioblastoma. Promoter genotyping was performed on brain tumor tissue obtained from 81 patients and compared to 57 healthy individuals. The 2G/2G genotype is more prevalent in glioblastoma tissue compared to healthy individuals (p 5 0.01). mRNA and protein expression were measured in a subset of brain tumor and normal brain tissue samples. MMP-1 protein levels are significantly higher in glioblastoma tissue compared to normal brain (p 5 0.001). Electromobility shift assays and promoter assays were performed to assess binding capability and transcriptional activity, respectively. Proteins present in glioma cell lines can specifically bind the 2G promoter probe. MMP-1 transcription is significantly higher in cells transfected with the 2G promoter when compared to cells transfected with the 1G promoter (p<0.02). This polymorphism may provide a mechanism for increased expression of MMP-1 in malignant gliomas via elevation of MMP-1 mRNA transcription and may underlie the invasive phenotype. ' 2005 Wiley-Liss, Inc.Key words: brain tumors; matrix metalloproteinases; transcriptional regulation; SNP Gliomas account for 44% of all primary central nervous system tumors and of these the most common is the highly malignant glioblastoma multiforme (GBM). 1 Despite significant improvements in the diagnosis and treatment for patients with a GBM, this primary brain tumor remains essentially incurable. Although surgery and radiotherapy substantially improve patient survival, 2 95% of patients have a mean survival of 2 years following diagnosis. Patients foregoing treatment have a mean survival time of 4 months. The characteristic ability of GBMs to invade surrounding normal tissue makes total surgical resection virtually impossible.Matrix metalloproteinase-1 (MMP-1), also known as collagenase-1, is a member of the MMP family of zinc-dependent endopeptidases, which have the ability to cleave substrates in the extracellular matrix. Substrates for MMP-1 include collagen types I, II, III, VII and X, gelatin, entactin, aggrecan and tenascin. Until recently it was thought that MMPs were responsible mainly for the degradation of extracellular matrix components. However it has become clear that the MMP family has a wide range of other influences on biologic processes including the generation of bioactive proteins. [3][4][5] Examples include the cleavage of the proteo...

Transcriptional Repression of Matrix Metalloproteinase Gene Expression by the Orphan Nuclear Receptor NURR1 in Cartilage

“…We have demonstrated that ETS1 activates this region of the promoter in chondrocytes (Fig. 6C), and previous reports have shown that ETS and AP-1 factors bind to this site as part of a large protein complex (56,65,74,77). Our results indicate a functional antagonism between NURR1 and ETS1, where NURR1 reduces ETS1 induction of the MMP-1 promoter, and ETS1 blocks transactivation of the NBRE reporter (Fig.…”

Matrix Metalloproteinase Single-Nucleotide Polymorphisms and Haplotypes Predict Breast Cancer Progression

“…The haplotypes also reflect the previously described linkage disequilibrium between the MMP-1 2G allele and the MMP-3 5A allele (40). Polymorphisms in the promoters of MMPs have a functional role and have been shown to exhibit allelotypic effects on levels of gene transcript (15,32). Although the lifelong effects of altered transcription are unclear, overexpression of MMPs caused by promoter polymorphisms may enhance cancer progression by virtue of their role in degradation of the ECM, thereby generating an environment that favors tumor cell migration.…”

Exacerbation of Dopaminergic Terminal Damage in a Mouse Model of Parkinson's Disease by the G-Protein-Coupled Receptor Protease-Activated Receptor 1

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