MMP-9 Promoter Region Research Articles

Identifying the Regulative Role of NF-κB Binding Sites Within Promoter Region of Human Matrix Metalloproteinase 9 (mmp-9) by TNF-α Induction

Matrix metalloproteinase 9 (MMP-9), a member of MMP family, is involved in many physiological processes, including cardiovascular disease (CVD). Tumor necrosis factor-α (TNF-α) is considered a cytokine with pleiotropic biological capabilities and leads to the process of CVD when TNF-α is abnormally released and stimulates MMP-9 expression and activation. In this study, we investigated the molecular mechanism of TNF-α-regulated MMP-9 expression. The experimental results confirm that TNF-α could upregulate MMP-9 expression in heart myoblast H9c2 cells of rat. To evaluate the MMP-9 regulation at transcriptional level, a DNA fragment of 2.2 kb (-2168/+18) of human mmp-9 promoter region was cloned and constructed in a vector of luciferase reporter gene. The 2.2-kb sequences were identified as having three candidate nuclear factor-κ B (NF-κB) binding sites: NF-κB I (-1418/-1409), NF-κB II (-626/-617), and NF-κB III (-353/-345). A series of reporter vectors with the mutated NF-κB sites of mmp-9 promoter sequences were constructed and transfected into H9c2 cells. The results show that the NF-κB II binding site (-626/-617) within the promoter region of mmp-9 plays a key role in upregulation of mmp-9 expression by TNF-α induction. In addition, we also first identified that the NF-κB I, similar to c-Rel, might be one of the NF-κB families to regulate mmp-9 expression.

NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes

BackgroundMatrix metalloproteinase-9 (MMP-9) plays a crucial role in pathological processes of brain inflammation, injury, and neurodegeneration. Moreover, bradykinin (BK) induces the expression of several inflammatory proteins in brain astrocytes. Recent studies have suggested that increased oxidative stress is implicated in the brain inflammation and injury. However, whether BK induced MMP-9 expression mediated through oxidative stress remains virtually unknown. Herein we investigated the role of redox signals in BK-induced MMP-9 expression in rat brain astrocytes (RBA-1 cells).ResultsIn the study, we first demonstrated that reactive oxygen species (ROS) plays a crucial role in BK-induced MMP-9 expression in cultured brain astrocytes (in vitro) and animal brain tissue (in vivo) models. Next, BK-induced MMP-9 expression is mediated through a Ca2+-mediated PKC-α linking to p47phox/NADPH oxidase 2 (Nox2)/ROS signaling pathway. Nox2-dependent ROS generation led to activation and up-regulation of the downstream transcriptional factor AP-1 (i.e. c-Fos and c-Jun), which bound to MMP-9 promoter region, and thereby turned on transcription of MMP-9 gene. Functionally, BK-induced MMP-9 expression enhanced astrocytic migration.ConclusionsThese results demonstrated that in RBA-1 cells, activation of AP-1 (c-Fos/c-Jun) by the PKC-α-mediated Nox2/ROS signals is essential for up-regulation of MMP-9 and cell migration enhanced by BK.

Polymorphism of metalloproteinases and inhibitors of matalloproteinases in patients with varicose veins

Objective To study the relationship between human metalloproteinases (MMP-9),endogenous tissue inhibitors of matalloproteinases (TIMP-2) promoters single nucleotide polymorphisms (SNP) and varicose vascular remodeling in 60 cases of varicose vein and 60 normal controls.Methods Varicose vein group and control group were set up.We took 5 ml venous blood from every person of two groups,then extracted genomic DNA with QIAGEN blood extraction kit,and analyzed MMP-9/TIMP-2promoter region SNPs genotyping by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).Results In varicose vein group,there were 54 cases of homozygosity and 6 cases of heterozygote for DNA/MMP-9,and there were 32 cases of homozygosity and 28 cases of heterozygote for DNA/TIMP-2.In control group,there were 44 cases of homozygosity and 16 cases of heterozygote for DNA/MMP-9,and there were 43 cases of homozygosity and 17 cases of heterozygote for DNA/TIMP-2.Conclusion The results suggest that gene polymorphisms in the MMP-9 and TIMP-2 promoter region are associated with varicose veins. Key words: Single nucleotide polymorphism; Metalloproteinases; Varicose vein

Matrix metalloproteinase (MMP)‐9 and VEGF gene interaction models and MMP‐9 plasma levels in preeclampsia and gestational hypertension

Preeclampsia (PE) is a major contributor to maternal mortality worldwide but its etiology remains unclear. Although epistasis is suggested to be an important contributor to complex diseases, only a few studies have addressed this issue in PE. We detect interaction models predictive of PE (n=122) and gestational hypertension (GH, n=107) between polymorphisms in the promoter region of MMP‐9 (C‐1562T) and VEGF (G‐634C) genes using robust multifactor dimensionality reduction (RMDR) method. This best model of interaction included the ‐1562CT genotype and the ‐ 1562T allele was previously associated with increased MMP‐9 expression. However, previous findings showed no significant differences in plasma MMP‐9 levels in women with PE when single genotypes or MMP‐9 haplotypes were considered. Therefore, we investigate if gene‐gene interactions were associated with MMP‐9 levels in PE and GH. We observed only a marginally association finding (P=0.055) in GH. Indeed, the origin of plasma MMP‐9 levels is unknown, and it is possible that fetal MMP‐9 genotypes, tissue inhibitors of MMPs (TIMPs) and environmental factors may also contribute to the plasma MMP‐9 levels. We characterized interactions among genes related to angiogenesis and endothelial dysfunction seen in PE. Moreover, our study also provides further insights in the pathophysiology of PE and GH. Research support: CNPq, FAPESP and CAPES

Influence of single nucleotide polymorphisms in the MMP1 promoter region on cutaneous melanoma progression

Recently, we reported on the associations of seven single nucleotide polymorphisms (SNPs) in the promoter region of MMP1 gene with susceptibility to cutaneous melanoma (CM). Considering the reported correlation between MMP1 expression and melanoma progression, we hypothesized that these promoter SNPs might affect CM progression and prognosis. In this study, we examined the associations of seven SNPs with overall survival, as well as six clinicopathological factors in 754 patients with CM. After adjustment for 11 covariates, we observed significant associations of the SNP -422A>T (rs475007) with ulceration status (P=0.012), primary tumor thickness (P=0.040), and anatomic site (P=0.030). We also observed significant associations of the SNP -755T>G (rs498186) with ulceration status (P=0.038) and anatomic site (P=0.003). Two SNPs, -839G>A and -519A>G, were marginally associated with primary tumor thickness, ulceration status, and anatomic site. Furthermore, the frequency of haplotype 2G-G-G-A-A-G-T was higher in patients with ulceration (odds ratio=2.18, 95% confidence interval: 1.08-4.40, P=0.030) compared with those without ulceration. However, we did not find significant associations of these SNPs with overall survival and other clinical factors. 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.

Association between Polymorphisms in the Promoter Regions of Matrix Metalloproteinases (MMPs) and Risk of Cancer Metastasis: A Meta-Analysis

BackgroundA variety of studies have evaluated the associations between polymorphisms in the promoter regions of Matrix metalloproteinases (MMPs) and cancer metastasis. However, the results remain inconclusive. To better understand the roles of MMP polymorphisms in metastasis, we conducted a comprehensive meta-analysis.MethodsElectronic databases were searched (from January 2000 to June 2011) for any MMP genetic association studies in metastasis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the associations between MMP polymorphisms and metastasis. Statistical analysis was performed with Review Manager 5.0 and STATA11.0.ResultsThirty-three studies addressing five MMP polymorphisms were analyzed among 10,516 cancer cases (4,059 metastasis-positive cases and 6,457 metastasis-negative cases). For MMP1 (−1607)1G/2G, genotype 2G/2G increased the overall risk of metastasis under the recessive model (OR = 1.44, 95% CI = 1.05–1.98). In subgroup analysis based on cancer type, associations were found in head/neck and breast cancer under the recessive model, and also in breast cancer under the dominant model. For MMP3 (−1171) 5A/6A, the polymorphism decreased the overall risk of metastasis under two genetic models (recessive: OR = 0.80, 95%CI = 0.64–0.99, dominant: OR = 0.72, 95%CI = 0.56–0.93). The polymorphisms of MMP7 (−181) A/G and MMP9 (−1562) C/T increased metastatic risk. However, no association was observed between MMP2 (−1306) C/T and metastasis.ConclusionsOur investigations demonstrate that polymorphisms in the promoter regions of MMP1, 3, 7 and 9 might be associated with metastasis in some cancers. Further studies with large sample size for MMP2 should be conducted.

Pure coronary ectasia differs from atherosclerosis: Morphological and risk factors analysis

Coronary artery ectasia (CAE) is defined as localized coronary dilatation that exceeds the diameter of the normal adjacent segments or the diameter of the patients' largest coronary artery by 1.5 times [ [1] Syed M. Lesch M. Coronary artery aneurysm: a review. Prog Cardiovasc Dis. 1997; 40: 77-84 Google Scholar ]. The prevalence of the disease varies between 1.5 and 5% with an occurrence rate of 10% among Indians, and with male predominance [ 2 Giannoglou G.D. Antoniadis A.P. Chatzizisis Y.S. Damvopoulou E. Parcharidis G.E. Louridas G.E. Prevalence of ectasia in human coronary arteries in patients in northern Greece referred for coronary angiography. Am J Cardiol. 2006; 98: 314-318 Google Scholar , 3 Sharma S.N. Kaul U. Sharma S. et al. Coronary arteriographic profile in young and old Indian patients with ischaemic heart disease: a comparative study. Indian Heart J. 1990; 42: 365-369 Google Scholar ]. Such variation in disease prevalence is related to other associated conditions e.g. Kawasaki disease [ [4] Newburger J.W. Burns J.C. Kawasaki disease. Vasc Med. 1999; 4: 187-202 Google Scholar ] and connective tissue disorders, e.g. particularly polyarteritis nodosa [ [5] Pick R.A. Glover M.U. Vieweg W.V. Myocardial infarction in a young woman with isolated coronary arteritis. Chest. 1982; 82: 378-380 Google Scholar ] and Takayasu arteritis [ [6] Suzuki H. Daida H. Tanaka M. et al. Giant aneurysm of the left main coronary artery in Takayasu aortitis. Heart. 1999; 81: 214-217 Google Scholar ]. Despite the documented etiological role of atherosclerois [ [7] Antoniadis A.P. Chatzizisis Y.S. Giannoglou G.D. Pathogenetic mechanisms of coronary ectasia. Int J Cardiol. 2008; 130: 335-343 Google Scholar ], it fails to explain the paradoxically low prevalence of CAE among diabetics [ [8] Androulakis A.E. Andrikopoulos G.K. Kartalis A.N. et al. Relation of coronary artery ectasia to diabetes mellitus. Am J Cardiol. 2004; 93: 1165-1167 Google Scholar ], the anatomical predominance of the right coronary artery (RCA) [ [9] Farto e Abreu P. Mesquita A. Silva J.A. Seabra-Gomes R. Coronary artery ectasia: clinical and angiographic characteristics and prognosis. Rev Port Cardiol. 1993; 12: 305-310 Google Scholar ], the histological loss of the musculo-elastic component of the arterial wall [ [10] Markis J.E. Joffe C.D. Cohn P.F. Feen D.J. Herman M.V. Gorlin R. Clinical significance of coronary arterial ectasia. Am J Cardiol. 1976; 37: 217-222 Google Scholar ] and the potential genetic polymorphisms found in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 [ [11] Lamblin N. Bauters C. Hermant X. Lablanche J.M. Helbecque N. Amouyel P. Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease. J Am Coll Cardiol. 2002; 40: 43-48 Google Scholar ]. We hypothesized that CAE has different nature from that of atherosclerotic coronary artery disease (CAD). We therefore examined consecutive coronary angiograms performed at the Umeå Heart Centre, Sweden and Letterkenny General Hospital, Ireland, between 2003 and 2009, with the objective of identifying all patients diagnosed as having CAE (Fig. 1), described the exact angiographic findings and analyzed the cardiovascular risk factors. Patients were classified as having pure or mixed lesions according to the following criteria. Pure CAE (Fig. 2A and C) when there was no evidence for atherosclerosis and mixed CAE (Fig. 2B and D) when, in addition to the dilated segments, there was classical evidence for atherosclerotic changes (plaque formation or minor atheromata ≤10% of lumen narrowing). We also recorded the anatomical sites of ectatic arteries and any ectatic lesion exceeding 20 mm in length. Patients with evidence for prior coronary intervention or other cardiac conditions were excluded. Clinical and angiographic variables of patients with CAE were later compared with 37 age-matched controls (65±8 years, 13 male) who were found to have normal angiograms. Conventional statistics including unpaired Student t test, chi-square test, univariate and multiple logistic regression analyses were used with p<0.05 as significance. Fig. 2Image showing the quantitative angiographic diferences between Pure (A, C) and mixed CAE (B, D). View Large Image Figure Viewer Download Hi-res image

IL‐1β induces MMP‐9 expression associated with cell migration via a c‐Src‐dependent PDGFR/EGFR transactivation in A549 cells

IL-1β has been shown to induce MMP-9 expression which is regulated by MAPKs and NF-κB in various cell types. IL-1β also stimulates transactivation of growth factor receptors and PI3K/Akt, leading to the expression of inflammatory proteins. Here, we investigated whether these transactivation mechanisms participated in IL-1β-induced MMP-9 expression in A549 cells. Inhibition of MMP-9 expression by the inhibitors of Src (PP1), PDGFR (AG1296), and EGFR (AG1478) or transfection with siRNA of Src and Akt prevented IL-1β-induced cell migration in A549 cells. The involvement of these tyrosine kinases in these responses was mediated through phosphorylation of Src, PDGFR, or EGFR via the formation of Src/PDGFR or Src/EGFR complex which was attenuated by PP1. Moreover, IL-1β-induced MMP-9 expression through EGFR transactivation was diminished by the inhibitors of MMPs and heparin-binding EGF-like factor (HB-EGF), or neutralizing HB-EGF antibody. Moreover, IL-1β-stimulated activation and translocation of Akt and NF-κB (p65), and then the activated NF-κB (p65) recruited to MMP-9 promoter region, which was attenuated by pretreatment with LY294002. These results suggested that IL-1β-induced MMP-9 expression and cell migration was mediated via transactivation of Src/EGFR/PDGFR/Akt/NF-κB in A549.

Developmental arrest of scNT‐derived fetuses by disruption of the developing endometrial gland as a result of impaired trophoblast migration and invasiveness

Somatic cell nuclear transfer (scNT)-derived pig placenta tissues of gestational day 30 displayed avascularization and hypovascularization. Most of the cytotrophoblast-like cells of the developing scNT-derived placenta villi were improperly localized or exhibited impaired migration to their targeting loci. Id-2, Met, MMP-9, and MCM-7 were barely detectable in the cytotrophoblast cells of the scNT-derived placenta villi. Active MMP-2 and MMP-9 expression was significantly down-regulated in the scNT-embryo transferred recipient uteri. scNT clones exhibited a hypermethylated pattern within the pig MMP-9 promoter region and the significance of GC box in the regulation of MMP-9 promoter activity. Marked apoptosis was observed in the developing endometrial gland of scNT-embryo transferred recipient uteri. Collectively, our data strongly indicated that early gestational death of scNT clones is caused, at least in part, by disruption of the developing endometrial gland as a result of impaired trophoblast migration and invasiveness due to the down-regulation of active MMP-9 expression.

Polymorphisms in MMP-9 and TIMP-2 in Chinese Patients with Varicose Veins

Varicose veins (VVs), a common vascular disease, are functionally characterized by dilation and tortuosity and are widely prevalent in the adult population. The pathophysiology and molecular mechanism of VVs are still unclear. A genetic risk for VVs has been demonstrated, although no genetic variant pertaining to VVs has been identified. Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), which can prevent excessive extracellular matrix (ECM) degradation, greatly impact vascular remodeling and may play a vital role in patients with VVs. We evaluated a potential association between polymorphisms in the promoters of MMP-9 and TIMP-2 and the risk for VVs in the Chinese population. Genotyping of the promoter region polymorphisms -1562C/T in MMP-9 and -418G/C in TIMP-2 was performed with PCR and restriction fragment length polymorphism (PCR-RFLP) assays with a group of 60 patients with VVs and 60 healthy controls. Purified PCR products were sequenced. A significant correlation was found between patients with VVs and controls at -1562C/T in MMP-9. The TIMP-2 gene polymorphism -418G/C was also associated with VVs. Our results suggest that polymorphisms in the promoter region of MMP-9 and TIMP-2 are associated with VVs in the Chinese population.

Functional polymorphism of the MMP-1 promoter (-1607 1G/2G) in potentially malignant and malignant head and neck lesions in an Indian population

Matrix metalloproteinases (MMP) are a family of zinc-dependent proteases that degrade the entire component of the extracellular matrix. Our study explores the association of the MMP1 gene promoter (-1607 1G/2G) polymorphisms in oral submucous fibrosis (OSMF) and head and neck squamous cell carcinoma (HNSCC) in an Indian population. The MMP1single-nucleotide polymorphism (SNP) was genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis in 412 patients with OSMF, 422 with HNSCC and 426 controls. Our results showed that the frequency of 1G/2G or 2G/2G promoter genotypes having the 2G allele is associated with higher enzymatic activity and significantly increases in OSMF (p<0.001) and HNSCC cases (p<0.00). In this study, results concluded that SNPs in the MMP1 promoter region may be associated with susceptibility to OSMF as well as HNSCC in an Indian population and addiction habits such as areca nut chewing and alcohol abuse may enhance the expression of the 2G allele of MMP1 genes in OSMF and HNSCC cases.

IL‐1β induces expression of matrix metalloproteinase‐9 and cell migration via a c‐Src‐dependent, growth factor receptor transactivation in A549 cells

Interleukin (IL)-1beta-induced matrix metalloproteinase (MMP-9) expression is regulated by mitogen activated protein kinases (MAPKs) and NF-kappaB. IL-1beta also stimulates transactivation of growth factor receptors and phosphatidylinositol 3-kinase (PI3K)/Akt., leading to the expression of inflammatory proteins. Here, we investigated whether these transactivation mechanisms participated in IL-1beta-induced MMP-9 expression in A549 cells. A549 cells were treated with/without pharmacological inhibitors and neutralizing antibody or transfected with dominant negative mutants and siRNA of particular protein kinases before stimulation with IL-1beta. Cell migration was measured by in vitro scratch assay. Expression and enzymatic activity of MMP-9 were analysed by Western blot and gelatin zymography. Transcriptional activity of MMP-9 was analysed by RT-PCR, chromatin immunoprecipitation and promoter assays. Inhibition of MMP-9 expression by inhibitors of Src (PP1), platelet-derived growth factor (PDGF) receptor and epithelial growth factor (EGF) receptor or transfection with siRNA for Src and Akt prevented IL-1beta-induced migration of A549 cells. These tyrosine kinases were involved through phosphorylation of Src, PDGF, or EGF receptors (EGFRs) via the formation of Src/PDGFR or Src/EGFR complexes, attenuated by PP1. IL-1beta-induced MMP-9 expression through EGFR transactivation was diminished by inhibitors of MMPs and heparin-binding EGF-like factor (HB-EGF), or a neutralizing HB-EGF antibody. IL-1beta-stimulated activation and translocation of Akt and NF-kappaB (p65); the recruitment of activated NF-kappaB (p65) to the MMP-9 promoter region was attenuated by LY294002. IL-1beta-induced MMP-9 expression and cell migration was mediated through c-Src-dependent transactivation of EGFR/PDGFR/PI3K/Akt linking to the NF-kappaB pathway in A549 cells.

Single nucleotide polymorphism in the MMP-9 gene is associated with susceptibility to develop multiple sclerosis in an Italian case-control study

To investigate the role of the matrix metalloproteinase-9 gene ( MMP-9) in multiple sclerosis (MS), we analyzed the functional − 1562C/T and − 90 (CA) n repeat polymorphisms in 243 Italian patients with MS and 173 healthy controls. A significant increase of the − 1562T allele carriers was found in patients with MS compared to controls. Moreover, haplotype analysis showed that the haplotype formed by the − 1562T allele and the L allele ((CA) ≤ 20 ) was over-represented in patients with MS versus controls. These results suggest that a genetic polymorphism of the MMP-9 promoter region may influence the susceptibility to MS.

HER2-mediated upregulation of MMP-1 is involved in gastric cancer cell invasion

HER2 overexpression is associated with metastasis—the main cause of death in individuals with gastric cancer. In this study, we demonstrated that vector-based shRNA significantly knocked down the expression of HER2 and considerably inhibited both the migration and invasion of gastric cancer cells. HER2 knockdown resulted in the downregulation of the expression of MMP-1, while HER2 overexpression improved the transcription of MMP-1 through the activation of an MMP-1 promoter. The promoter region of MMP-1 between −2500 and −2000 bp was found to be crucial for the upregulation of HER2-mediated transcription. Furthermore, a truncated promoter (−70 to + 63) did not display any transcriptional activity. Cell invasion activity was almost completely inhibited when MMP-1 was knocked down. Conversely, the overexpression of MMP-1 partly rescued the invasion ability of cell strains with knocked-down HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-1 may be required to effectively block HER2 signaling in gastric cancer therapy.

Polymorphisms in MMP-2 and MMP-9 promoter regions are associated with endometriosis

In this case-control study, we investigated the potential associations of MMP-2 and MMP-9 gene promoter region polymorphisms as well as MMP-2 promoter haplotypes with susceptibility to endometriosis in women of caucasian origin. The results demonstrated that polymorphisms in MMP-2 (-735 C/T) and MMP-9 (-1562 C/T) were associated with elevated risk of endometriosis and that certain MMP-2 promoter haplotypes were more common in control group.

A role for AP-1 in matrix metalloproteinase production and invadopodia formation of v-Crk-transformed cells

Both MMP-2 and MMP-9 play critical roles in tumor invasion, but their productions are differentially controlled. While the promoter region of MMP-9 has the conserved proximal AP-1 binding site, that of the MMP-2 has a noncanonical AP-1 site. To assess the role of AP-1 function, we examined the effects of dominant-negative Fos (ΔFos), BATF and siRNA against c-Jun on MMP production in v-Crk-transformed cells which have augmented production of MMP-2 and MMP-9. Suppression of AP-1 dependent transcription by conditional expression of dominant-negative Fos (ΔFos) and BATF substantially inhibited not only MMP-9 production but also MMP-2 production. The ChIP analysis showed the direct association of AP-1 and MMP-2 promoter region. In addition, silencing of c-Jun expression by siRNA transfection suppressed MMP-2 and MMP-9 production and in vitro invasiveness. Furthermore, the invadopodia formation of v-Crk-transformed cells could be suppressed by BATF expression or c-Jun siRNA treatment. Taken together, AP-1 appears to play a critical role in the production of MMP-2 and MMP-9 and invadopodia formation of v-Crk-transformed cells.

RECK Negatively Regulates Matrix Metalloproteinase-9 Transcription

RECK, a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of some matrix metalloproteinases (MMP), thereby suppressing tumor cell metastasis; however, the detailed mechanism is still obscure. In this study, we compared the gene expression profiles between mock- and RECK-transfected HT1080 cells and showed that RECK decreases MMP-9 mRNA levels but not other MMP mRNA levels. Moreover, treatment with RECK-specific siRNA increased MMP-9 mRNA in RECK-expressing cells. The promoter assay showed that MMP-9 promoter activity was suppressed by RECK and that RECK-mediated suppression of MMP-9 promoter activity requires 12-O-tetradecanoylphorbol-13-acetate-responsive element (TRE) and kappaB sites. Moreover, the binding ability of Fra-1 and c-Jun to TRE within the MMP-9 promoter region was suppressed by RECK. Thus, these results show that RECK is a negative regulator of MMP-9 transcription.

Yin Yang 1 Is a Critical Repressor of Matrix Metalloproteinase-9 Expression in Brain Neurons

Membrane depolarization controls long lasting adaptive neuronal changes in brain physiology and pathology. Such responses are believed to be gene expression-dependent. Notably, however, only a couple of gene repressors active in nondepolarized neurons have been described. In this study, we show that in the unstimulated rat hippocampus in vivo, as well as in the nondepolarized brain neurons in primary culture, the transcriptional regulator Yin Yang 1 (YY1) is bound to the proximal Mmp-9 promoter and strongly represses Mmp-9 transcription. Furthermore, we demonstrate that monoubiquitinated and CtBP1 (C-terminal binding protein 1)-bound YY1 regulates Mmp-9 mRNA synthesis in rat brain neurons controlling its transcription apparently via HDAC3-dependent histone deacetylation. In conclusion, our data suggest that YY1 exerts, via epigenetic mechanisms, a control over neuronal expression of MMP-9. Because MMP-9 has recently been shown to play a pivotal role in physiological and pathological neuronal plasticity, YY1 may be implicated in these phenomena as well.

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

Polymorphisms within the promoter region of several matrix metalloproteinase (MMP) genes have been linked to alterations in the level of transcription. We hypothesized that an individual's MMP genotype and haplotype will influence breast tumor progression and help predict prognosis. This study has evaluated the association between single-nucleotide polymorphisms (SNP) in the promoter regions of MMP-1, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13 and metastatic spread of breast cancer in 128 lymph node-negative and 93 lymph node-positive patients. The study cohort was of mixed ethnicity, with Caucasian patients comprising 65%. Associations between genotype and lymph node status were estimated by logistic regression and with overall survival using the method of Kaplan-Meier and log-rank test. Associations between haplotype and lymph node status were also investigated. The data show a significant and independent association of the C/T genotype for MMP-9 [mixed ethnicities odds ratio 3.6, 95% confidence interval (95% CI) 1.2-11.1; Caucasian odds ratio 9.1, 95% CI 1.7-48.4] and the 2G/2G genotype for MMP-1 (mixed ethnicities odds ratio 3.9, 95% CI 1.7-9.4; Caucasian odds ratio 2.6, 95% CI 1.0-6.9) with lymph node-positive disease. MMP-1 2G/2G was associated with reduced survival (hazard ratio 3.1, 95% CI 1.1-8.7), although this is dependent on lymph node status. Two haplotypes, driven by the MMP-1 2G allele, were significantly associated with lymph node-positive disease and survival. These results suggest that MMP single-nucleotide polymorphisms influence breast cancer behavior and that the MMP-1 2G/2G genotype increases the risk of lymph node metastasis and predicts poor prognosis.

The 2G allele of promoter region of Matrix metalloproteinase-1 as an essential pre-condition for the early onset of oral squamous cell carcinoma

BackgroundMatrix metalloproteinase (MMP) is known to be involved in the initial and progressive stages of cancer development, and in the aggressive phenotypes of cancer. This study examines the association of single nucleotide polymorphisms in promoter regions of MMP-1 and MMP-3 with susceptibility to oral squamous cell carcinoma (OSCC).MethodsWe compared 170 Japanese OSCC cases and 164 healthy controls for genotypes of MMP-1 and MMP-3.ResultsThe frequency of the MMP-1 2G allele was higher and that of the 1G homozygote was lower in the OSCC cases (p = 0.034). A multivariate logistic regression analysis revealed that subjects who were 45 years old or older had a significantly increased (2.47-fold) risk of OSCC (95%CI 1.47–4.14, p = 0.0006), and those carrying the MMP-1 2G allele had a 2.30-fold risk (95%CI 1.15–4.58, p = 0.018), indicating independent involvement of these factors in OSCC. One of the key discoveries of this research is the apparent reduction of the MMP-1 1G/1G and 1G/2G genotype distributions among the early onset OSCC cases under the ages of 45 years. It should be noted that the tongue was the primary site in 86.2% of these early onset cases. This could suggest the specific carcinogenic mechanisms, i.e. specific carcinogenic stimulations and/or genetic factors in the tongue.ConclusionSince the 2G allele is a majority of the MMP-1 genotype in the general population, it seems to act as a genetic pre-condition in OSCC development. However this report suggests a crucial impact of the MMP-1 2G allele in the early onset OSCC.