The role of genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes in head and neck cancer

Department of Head and Neck Surgery, Faculty of Medicine, Siriraj Hospital Medical School, Mahidol University, 2 Prannok Road, Bangkok 10700, Thailand.
Oral Oncology (Impact Factor: 3.61). 03/2006; 42(3):257-67. DOI: 10.1016/j.oraloncology.2005.07.008
Source: PubMed


Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) play an important role in several stages of cancer initiation and development. Single nucleotide polymorphisms identified in the promoters of MMP2 (-1306C-->T) and TIMP2 (-418G-->C) abolish the Sp1-binding site and thus may down-regulate expression of the genes. We examined the contribution of these polymorphisms to susceptibility and aggressiveness of head and neck squamous cell carcinoma (HNSCC). MMP2 genotypes were determined by PCR-based allele-specific refractory mutation analysis and TIMP2 genotypes identified by PCR-RFLP in a panel of HNSCC cell lines and in 239 head and neck cancer patients and 250 frequency matched controls in an ethnic Thai population. We found that subjects with the MMP2 CC genotype was associated with significantly increased risk [adjusted odds ratio (OR), 1.97; 95% confidence interval (95% CI), 1.23-3.15] for developing HNSCC compared with those with the variant genotype (-1306CT or TT). For TIMP2, a moderately increased risk of the cancer (OR, 1.43; 95% CI, 0.98-2.08) was also associated with the variant allele (-418GC or CC), compared with the GG common allele. Furthermore, the polymorphisms in both genes showed some additive effect and the highest risk for head and neck cancer was observed in those with MMP2 CC genotype and TIMP2 variant GC or CC genotype (OR, 2.34; 95% CI, 1.31-4.18). A correlation between promoter polymorphisms and the levels of mRNA expression in cell lines and cancer tissues was found. Finally, the MMP2 CC genotype was correlated with adverse clinicopathological variables. These findings suggest that the genetic polymorphisms in the promoters of MMP2 and TIMP2 may be associated with the development and aggressiveness of HNSCC.

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    • "The polymorphisms of MMP-2 (-1306 C/T) and TIMP-2 (-418 G/C) located at the SP1 binding site of the promoter region and the substitution of C to T and G to C may result in down-regulation of MMP-2 and TIMP-2 genes, respectively, by eliminating the SP1 binding site. Therefore, studies have investigated the role of these polymorphisms as risk factors for several diseases [17] [18]. This study investigated the potential association between MMP-2 (-1306 C/T) and TIMP-2 (-418 G/C) polymorphisms and the risk for acne in a Turkish population. "
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    ABSTRACT: Acne, a chronic inflammatory skin disease, can be seen at any age but it most often occurs in adolescents and young people. Several factors, including increased sebum production, abnormal cornification of the pilosebaceous units, proliferation of Propionibacterium acne, and extracellular matrix (ECM) remodeling, are thought to be associated with the pathogenesis of the acne. The remodeling of the ECM is regulated by a balance between matrix metalloproteinases (MMPs) and their inhibitors called tissue inhibitors of metalloproteinases (TIMPs). The current study investigated the potential association between MMP-2 (-1306 C/T) and TIMP-2 (-418 G/C) polymorphisms and the risk for acne in a Turkish population. The study was conducted with 85 subjects who presented to the Dermatology Department of Duzce University Hospital. DNA was isolated from 2 ml of peripheral blood taken from each subject, and their genotypes were analyzed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The CC, CT, and TT genotypes for MMP-2 (-1306 C/T) polymorphism were similar between the patient and control group (24 [55.8%], 17 [39.5%], and 2 [4.7%], respectively, vs. 21 [50%], 18 [42.9%], and 3 [7.1%], respectively). However, the distribution of the GG, GC, and CC genotypes for TIMP-2 (-418 G/C) polymorphism were different between the patient and control group (30 [69.8%], 9 [14.8%] and 4 [9.3%], respectively, vs. 26 [61.9%], 14 [33.3%], and 2 [4.8%], respectively). The results demonstrated that the TIMP-2 (-418 CC) genotype was nearly two times more common in the patient group compared to the control group (p=0.686, OR=1.45). It may be possible that the TIMP-2 (-418 CC) genotype increases the tendency to develop acne vulgaris by disrupting the balance between MMPs and TIMPs. Further investigations are needed to clarify more precisely the relationship between acne and MMP-TIMP genes.
    Full-text · Article · Nov 2013 · International Journal of Clinical and Experimental Medicine
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    • "for developing HNSCC compared with those with the variant genotype (-1306 CT or TT). These findings suggested that the genetic polymorphisms in the promoters of MMP-2 may be associated with the development and aggressiveness of HNSCC [51]. Lin et al reported that MMP-2 -1306 C>T polymorphism in buccal squamous cell carcinoma (BSCC) and non buccal squamous cell carcinoma (NBSCC). "
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    ABSTRACT: Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are capable of cleaving all extra cellular matrix (ECM) substrates. Degradation of matrix is a key event in progression, invasion and metastasis of potentially malignant and malignant lesions of the head and neck. It might have an important polymorphic association at the promoter regions of several MMPs such as MMP-1 (-1607 1G/2G), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T) and TIMP-2 (-418 G/C or C/C). Tissue inhibitors of metalloproteinases (TIMPs) are naturally occurring inhibitors of MMPs, which inhibit the activity of MMPs and control the breakdown of ECM. Currently, many MMP inhibitors (MMPIs) are under development for treating different malignancies. Useful markers associated with molecular aggressiveness might have a role in prognostication of malignancies and to better recognize patient groups that need more antagonistic treatment options. Furthermore, the introduction of novel prognostic markers may also promote exclusively new treatment possibilities, and there is an obvious need to identify markers that could be used as selection criteria for novel therapies. The objective of this review is to discuss the molecular functions and polymorphic association of MMPs and TIMPs and the possible therapeutic aspects of these proteinases in potentially malignant and malignant head and neck lesions. So far, no promising drug target therapy has been developed for MMPs in the lesions of this region. In conclusion, further research is required for the development of their potential diagnostic and therapeutic possibilities.
    Full-text · Article · Feb 2010 · Journal of Biomedical Science
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    ABSTRACT: DNA sequence variations contribute to inter-individual variability in susceptibility to and/or severity of common diseases such as cancer, diabetes, and asthma. About 90% of all sequence variations in the human genome are single nucleotide polymorphisms. Each single nucleotide polymorphism arises from a single nucleotide substitution, resulting in the presence of two alleles which differ by one base pair of DNA. The second most common form of DNA sequence variation is microsatellite polymorphism, which is also known as short tandem repeat polymorphism. A microsatellite is a run of tandem repeats of a short DNA sequence, usually 1–4 base pairs. A microsatellite polymorphism can be di-allelic or multi-allelic, with the different alleles differing in the number of repeat units, and hence in length. It is likely that only a very small percentage of DNA sequence variations in the human genome are functionally important, exerting effects on gene expression or function. A DNA sequence variant that is functionally neutral can still be found to be associated with disease susceptibility, arising from linkage disequilibrium with a functional variant located on the same chromosome. Identification of genetic variants that contribute to disease susceptibility and/or severity can provide understanding of the molecular basis of the disease, could have diagnostic and prognostic value, and may provide useful molecular targets for developing novel therapeutics. There is evidence suggesting that polymorphisms in certain matrix metalloproteinase (MMP) genes could influence cancer susceptibility and/or prognosis. This chapter will highlight some of these findings, focusing on MMP1, MMP2, MMP3, MMP9, and MMP12.
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