Matrix Metalloproteinase-9 Gene Research Articles

Muscle Regeneration in Holothurians without the Upregulation of Muscle Genes.

The holothurian Eupentacta fraudatrix is capable of fully restoring its muscles after transverse dissection. Although the regeneration of these structures is well studied at the cellular level, the molecular basis of the process remains poorly understood. To identify genes that may be involved in the regulation of muscle regeneration, the transcriptome of the longitudinal muscle band of E. fraudatrix has been sequenced at different time periods post-injury. An analysis of the map of biological processes and pathways has shown that most genes associated with myogenesis decrease their expression during the regeneration. The only exception is the genes united by the GO term "heart valve development". This may indicate the antiquity of mechanisms of mesodermal structure transformation, which was co-opted into various morphogeneses in deuterostomes. Two groups of genes that play a key role in the regeneration have been analyzed: transcription factors and matrix metalloproteinases. A total of six transcription factor genes (Ef-HOX5, Ef-ZEB2, Ef-RARB, Ef-RUNX1, Ef-SOX17, and Ef-ZNF318) and seven matrix metalloproteinase genes (Ef-MMP11, Ef-MMP13, Ef-MMP13-1, Ef-MMP16-2, Ef-MMP16-3, Ef-MMP24, and Ef-MMP24-1) showing differential expression during myogenesis have been revealed. The identified genes are assumed to be involved in the muscle regeneration in holothurians.

Effect of Secretome-Hypoxia Mesenchymal Stem Cells on Regulating SOD and MMP-1 mRNA Expressions in Skin Hyperpigmentation Rats

BACKGROUND: Ultraviolet B (UVB) radiation is the main factor causing hyperpigmentation. MSC secretome contains bioactive soluble molecules such as cytokines and growth factors that can accelerate skin regeneration. However, the molecular role of the secretome in hyperpigmentation is still unclear. AIM: This study aimed to determine the effect of secretome hypoxia mesenchymal stem cells (S-HMSC) gel on the expression of superoxide dismutase (SOD) and matrix metalloproteinases (MMP-1) genes in skin tissue of hyperpigmented rats induced by UVB light exposure. MATERIALS AND METHODS: Experimental research with post-test only control group. The control, base gel, T1 and T2 groups were UVB irradiated 6 times in 14 days at 302 nm with an minimal erythema dose of 390 mJ/cm2, respectively, while sham group did not receive UVB exposure. T1 was given 100 uL of S-HMSC gel and T2 was given 200 uL of S-HMSC gel every day for 14 days, while base gel received base gel. On day 15, skin tissue was isolated and analyzed for SOD and MMP-1 expression using qRT-PCR. RESULTS: The relative expression of the SOD gene in the treatment group (P1 = 0.47 ± 0.20, P2 = 1.22 ± 0.47) increased with increasing dose compared to the control group (UVB = 0.05 ± 0.01, Base gel = 0.05 ± 0.02). The relative expression of the MMP-1 gene in the treatment group (T1 = 5.82 ± 1.16, T2 = 2.86 ± 1.57) decreased with increasing dose compared to the control group (Control = 10.10 ± 2.31, and Base gel = 9.55 ± 1.29). CONCLUSION: Administration of S-HMSC gel can increase SOD gene expression and decrease MMP-1 gene expression in skin tissue of hyperpigmented rats model induced by UVB light.

Associative role of polymorphism of the gene of <i>MMP-9</i> (rs11697325) in development of arterial hypertension in patients with the rheumatoid arthritis

Aim. To study a contribution of polymorphism A-8202G (rs11697325) of a gene of matrix metalloproteinase-9 (MMP-9) in development of arterial hypertension (AH) in patients with the rheumatoid arthritis (RA).
 Materail and methods. 143 patients with RA were examined, among which a group of patients with RA without AH (n=50) and a group of patients with RA in association with AH (n=93) were identified. Healthy volunteers (n=151) were also divided into 2 groups comparable in age, sex and number with the main groups (control group 1 n=54, control group 2 n=97). The work used a range of clinical, laboratory, instrumental methods. A molecular genetic study was also performed. Blood samples were taken from all study participants. DNA isolation was carried out by the standard phenol-chloroform method. Genotyping for the MMP-9 gene was performed by PCR-RFLP analysis (polymerase chain reaction restriction fragment length polymorphism). PCR was carried out with a set of primers to the corresponding regions of the genome. PCR products were analyzed by electrophoresis in 4% polyacrylamide gel followed by staining with ethidium bromide.
 Results. In the course of a molecular genetic study, a statistically significant predominance of the homozygous AA genotype and the A allele of the MMP-9 (rs11697325) gene polymorphism was observed in the group of patients with RA, both separately and in association with AH, in comparison with the data of control groups. The risk of developing RA estimated by the odds ratio (OR) in carriers of the AA genotype of the MMP-9 gene is 1.8 times higher (95% confidence interval CI 1.1362.950; p=0.02) than in carriers of the GG and GA genotypes; in carriers of the A allele, the risk of developing RA is 1.6 times higher compared to the G allele (95% CI 1.1192.578; p=0.01). The OR risk of developing RA in association with hypertension in carriers of the AA genotype of the MMP-9 gene is 2.8 times higher (95% CI 1.2836.54; p=0.04) compared to GA and GG genotypes, 2.1 times higher in carriers of the A allele (95% CI 1.1134.127; p=0.02) compared to the G allele.
 Conclusion. Thus, the results of the study indicate that the homozygous AA genotype and the A allele of the MMP-9 (rs11697325) gene polymorphism are the predictors of the development of RA both as a separate nosological unit and in association with AH.

The role of rs3025058 polymorphism in the development of ischemic stroke in patients with cardiovascular diseases (review)

Acute cerebrovascular accident (ACC) is a formidable complication of a number of cardiovascular diseases, in a significant percentage of cases leading to disability and mortality. The literature available to us provides information on the role of type 3 matrix metalloproteinase gene (MMP-3) polymorphism in the development of stroke. It is believed that MMP-3 plays an important role in the natural processes of tissue remodeling and pathological processes. The mechanism of regulation of tissue remodeling MMP-3 is based on the activation of procollagenase-1. The associations of the single-nucleotide variant rs3025058 (5A/6A) with the development of ONMK in patients with cardiovascular pathology and risk factors of its development for the implementation of measures of primary prevention of this disease are considered. The article discusses issues related to the role and identification of associations of the single nucleotide variant rs3025058 (5А/6А) with the development of stroke in patients with cardiovascular pathology. When preparing the review, publications were searched in the MEDLINE/PubMed, Scopus, Cochrane Library, PEDro, eLIBRARY databases and Google Scholar. In preparing the literature review, the analysis of publications for the last 15 years is carried out. Represented evidence suggests the need for further study and effective use of the results of the study of the rs3025058 MMP-3 polymorphism for the implementation of primary prevention measures in the development of acute cerebrovascular accident, especially in the families of these patients.

Klotho Protein Decreases MMP-Mediated Degradation of Contractile Proteins during Ischaemia/Reperfusion Injury to the Cardiomyocytes

Ischaemia, followed by reperfusion, causes the generation of reactive oxygen species, overproduction of peroxynitrite, activation of matrix metalloproteinases (MMPs), and subsequently the degradation of heart contractile proteins in the cardiomyocytes. Klotho is a membrane-bound or soluble protein that regulates mineral metabolism and has antioxidative activity. This study aimed to examine the influence of Klotho protein on the MMP-mediated degradation of contractile proteins during ischaemia/reperfusion injury (IRI) to the cardiomyocytes. Human cardiac myocytes (HCM) underwent in vitro chemical IRI (with sodium cyanide and deoxyglucose), with or without the administration of recombinant Klotho protein. The expression of MMP genes, the expression and activity of MMP proteins, as well as the level of contractile proteins such as myosin light chain 1 (MLC1) and troponin I (TnI) in HCM were measured. Administration of Klotho protein resulted in a decreased activity of MMP-2 and reduced the release of MLC1 and TnI that followed in cells subjected to IRI. Thus, Klotho protein contributes to the inhibition of MMP-dependent degradation of contractile proteins and prevents injury to the cardiomyocytes during IRI.

Plasma Matrix Metalloproteinase-1 as a Prognostic Biomarker in Oral Cavity Squamous Cell Carcinoma.

Plasma matrix metalloproteinase-1 (MMP-1) is a collagenase encoded by the MMP-1 gene. However, the prognostic value of plasma MMP-1 levels in oral cavity squamous cell carcinoma (OSCC) has yet to be elucidated. The study is the first to use a cohort of OSCC patients to assess the association of plasma MMP-1 levels with clinicopathological factors/survival outcomes in OSCC patients. A total of 677 patients were retrospectively enrolled, including 276 oral potentially malignant disease (OPMD) and 401 OSCC patients from 2013 to 2021. Pretreatment plasma MMP-1 levels were measured with an enzyme-linked immunosorbent assay, and the values were compared between OPMD and OSCC patients. Furthermore, the association of plasma MMP-1 levels and clinicopathological characteristics/survival outcomes in OSCC patients was investigated. Plasma MMP-1 levels were significantly higher in OSCC patients than in OPMD patients (p = 0.04). In the OSCC group, plasma MMP-1 levels were significantly higher in females, tumor depth ≥10 mm, advanced pT classification and advanced overall stage (p = 0.04, <0.001, <0.001, 0.002, respectively). Higher plasma MMP-1 levels were significantly associated with poorer overall, disease-specific, disease-free, locoregional recurrence-free and distant metastasis-free survival (p = 0.003, 0.02, 0.005, 0.01, 0.001, respectively). Multivariate analysis revealed that plasma MMP-1 levels were a significant predictor for overall, disease-free, and distant metastasis-free survival (p = 0.03, 0.02, and 0.010, respectively). Plasma MMP-1 levels are associated with more severe clinicopathological manifestations and can also be regarded as a significant prognostic factor for OSCC posttreatment outcomes.

Expression and clinical significance of miR-17-5p in tumor tissues of patients with colorectal cancer

At present, there is a lack of novel biomarkers for the early diagnosis and targeted therapy of colorectal cancer (CRC). The current study investigated the expression of miR-17-5p in colorectal tumors and adjacent tissues, and examined the effects of miR-17-5p on the cellular growth of the colon cancer cell line HCT-116. A total of 30 paired tissue specimens were obtained from patients with CRC who were admitted to the Department of General Surgery V of the First Affiliated Hospital, Gannan Medical College between December 2019 and January 2021. The clinical information for the corresponding patients was collated. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was performed to detect the expression of miR-17-5p in tumor tissues and the paracancerous tissues. The relationship between miR-17-5p and clinicopathology was analyzed. The CRC cell line HCT-116 was transfected with miR-17-5p mimics and inhibitors using liposomes. The effects of miR-17-5p on cell proliferation, invasion and migration, and apoptosis were determined using colon formation assays, transwell and scratch assays, and flow cytometry, respectively. The effects of miR-17-5p on CD44 (homing cell adhesion molecule), MMP2 (matrix metalloproteinase 2), BCL2 (B-cell lymphoma-2), BAX (BCL2-associated X), and E-cadherin protein and gene expression were investigated using Western blot and RT-qPCR, respectively. MiR-17-5p expression was higher in tumor tissues compared to the normal adjacent tissues. While miR-17-5p expression levels were unrelated to age nor gender, they were related to the degree of differentiation, stage, lymph node metastasis, and tumor size in patients with CRC. Upregulation of miR-17-5p promoted CRC cell proliferation, metastasis, and invasion, while inhibiting apoptosis. However, downregulation of miR-17-5p had the opposite effect. Furthermore, miR-17-5p upregulation increased E-cadherin, CD44, MMP2, and BCL2 expression while decreasing BAX expression, whereas miR-17-5p downregulation had the opposite effect. MiR-17-5p is highly expressed in tumor tissues and correlates with increased proliferation, invasion, and migration, as well as reduced apoptosis in HCT-116 cells. Indeed, miR-17-5p may be a potential indicator for the early diagnosis of CRC and may guide clinical targeted therapy.

Role of G-protein coupled receptor (GPCRs)/(GPR-120) as an agonists in diabetic wound healing

Type 2 diabetes (T2D) or Obesity has been gradually rising throughout the globe. It is a major cause of noncommunicable illnesses such as cardiovascular disease type 2 diabetes (T2D), Nonalcoholic Steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and numerous malignancies, all of which have a negative effect on quality of natural life and life expectancy. Diabetic wound healing is hampered by a complicated pathophysiology combining immunological, metabolic factors and neuropathic. There are more than thirty GPCRs that have been occupied in the expansion or development of β-cell disfunction, insulin resistance, obesity, and T2DM Still, at current, only the GLP-1R has been effectively battered therapeutically. They play major function in gut hormone Secretion and appetite control adipogenesis, anti-inflammatory functions, antidiabetic functions. Diabeties is current treated by dressings, antidiabetic Drugs, growth factors such as (TGF1, FGF, EGF, VEGF and PDGF). Future therapeutic strategies will be based on single growth factor, multiple growth factor, skin, cytokine enhancer, cytokine antagonist, matrix metalloproteinase antagonist, gene therapy and stem cell therapy, extracellular matrix and angiogenesis. • GPCRs, transmit their signals mostly via the alpha subunits and Ga12/13, Gai/o, Gas, and Gaq/11, are the four main functional characteristics of their alpha subunits. • GPCRs, as indicated in the genesis or evolution of – insulin resistance, obesity and cell dysfunction, encouraged (T2DM). • GPCRs including as GPR65, GPR4, GPR132, and GPR68, are implicated in wound healing. • GPR120 is strongly stated in enteroendocrine cells, which promotes stomach inhibitory peptide production (GIP) and engaged in a well-coordinated anti-diabetic action.

C/EBP-β contributes to pig endometrial LE receptivity by targeting cell remodeling genes during implantation.

Transforming the endometrial luminal epithelium (LE) into a receptive state is a requisite event for successful embryo implantation. This study suggests the role of a transcription factor in regulating endometrial LE receptivity. The endometrial luminal epithelium (LE) undergoes extensive remodeling during implantation to establish receptivity of the uterus in response to the conceptus signals, such as interleukin 1β (IL1B). But the mechanisms remain to be fully understood. This study investigated the role of CCAAT/enhancer-binding protein β (C/EBP-β) in regulating pig endometrial LE receptivity. Our results showed that C/EBP-β was expressed and activated only in the endometrial LE in an implantation-dependent manner. In addition, C/EBP-β was highly activated at the pre-attachment stage compared to the attachment stage, and its activation was correlated with the expression of IL1B-dependent extracellular signal-regulated kinases1/2-p90 ribosomal S6 kinase signaling axis. Subsequent chromatin immunoprecipitation (ChIP)-sequencing analysis revealed that the binding of C/EBP-β within the promoter was positively associated with the transcription of genes related to cell remodeling. One such gene is matrix metalloproteinase 8 (MMP8), which is responsible for extracellular matrix degradation. The expression of MMP8 was abundant at the pre-attachment stage but dramatically declined at the attachment stage in the endometrial LE. Consistent with C/EBP-β, the expression and activation of MMP8 were limited to the endometrial LE in an implantation-dependent manner. Using ChIP-qPCR and electrophoresis mobility shift assay approaches, we demonstrated that C/EBP-β regulated the expression of the MMP8 gene during implantation. Furthermore, we detected that MMP8 and one of its substrates, type II collagen, showed a mutually exclusive expression pattern in pig endometrial LE during implantation. Our findings indicate that C/EBP-β plays a role in pig endometrial LE receptivity by regulating cell remodeling-related genes, such as MMP8, in response to conceptus signals during implantation.

Association of matrix metalloproteinase gene polymorphisms with different biological subtypes of breast cancer

Aim. To investigate the associations of matrix metalloproteinase (MMP) MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs17576 and rs3787268) gene polymorphisms with different biological subtypes of breast cancer (BC).&#x0D; Materials and methods. The study sample consisted of 285 patients with BC of various biological subtypes (luminal A and B [n=153], triple negative [n=108], and HER2 positive [HER2+, n=24]) and 746 females in the control group. Genotyping of four polymorphic sites of MMP3 (rs679620), MMP8 (rs1940475), and MMP9 (rs17576 and rs3787268) genes was performed in the study groups.&#x0D; Results. The role of MMP gene polymorphisms in the BC development of various biological subtypes differs. The c.836 AG MMP9 polymorphism (rs17576, the odds ratio is 0.670.71 for the G allele) has a protective effect on the development of luminal A- and B-subtypes of BC; susceptibility to triple-negative BC is associated with the polymorphic site c.1331-163 GA MMP9 (rs3787268, OR 4.51 for genotype AA), and two polymorphisms of the MMP3 (c.133 TC, rs679620, OR 0.460.49 for T allele) and MMP8 (c.259 TC, rs1940475, OR 0.370.48 for T allele) genes are associated with HER2+ BC development. According to the in silico data, the above polymorphisms have pronounced functional effects in organs and tissues that are pathogenetically significant for the disease, including the target organ, the breast.&#x0D; Conclusion. The c.836 AG MMP9 (rs17576) polymorphism is associated with luminal A- and B-subtype of BC; c.1331-163 GA MMP9 (rs3787268) is associated with triple negative BC, and c.133 TC MMP3 (rs679620) and c.259 TC MMP8 (rs1940475) are involved in HER2+ BC development.

Circulatory Maternal Endothelin 1 and Matrix Metalloproteinase-9 Gene Expression in PREECLAMPSIA: A Study in Western Uttar Pradesh, India.

Preeclampsia (PE) is a multiorgan disease of pregnant women. The main pathophysiology of PE is a trophoblastic invasion into maternal circulation leading to alterations in circulatory levels of matrix metalloproteinases (MMPs), inflammatory markers, and endothelin 1(ET1) levels. Therefore, the present study has explored the role of MMP-9 and ET1 and their association in PE. The advantage of the study is to provide insight into the pathology of PE. These markers may help in the early diagnosis and prognosis of PE. To investigate MMP-9 gene expression, ET1 level in PE cases and their correlation with blood pressure (BP), gestational age, weight, and height. The study design was a case-control observational study, which included 70 subjects in each case (PE) and controls (normal pregnant women (NPW)). Whole blood (250 ul) was utilized for RNA extraction (Trizol method) and synthesized cDNA as per manufacturer protocol. MMP-9 gene expression was analyzed by real-time PCR. Serum was utilized for ET1 estimation by sandwich ELISA. The ET1 levels and MMP-9 gene expression were significantly increased in preeclamptic women as compared to controls. There was no significant correlation between MMP-9 gene expression and serum ET1 levels. However, a significant moderate association between systolic BP and diastolic BP with ET1 levels and MMP9 gene expression was seen in both PE and NPW. A significantly increased circulatory concentration of ET1 and MMP-9 gene expression in PE might be used as an early diagnostic as well as a prognostic marker of PE.

Abstract 11782: Senolytic Therapy Improves Diastolic Cardiac Function in Aged Mice

Introduction: Cellular senescence, an irreversible arrest of the cell cycle, is a recognized hallmark of aging that contributes to age-related multi-organ dysfunction and diseases. Evidence suggests that cardiomyocyte senescence plays a critical role in the development of age-related cardiac dysfunction. We tested the hypothesis that targeting senescent cells via intermittent administration of the senolytic drugs dasatinib and quercetin (D&amp;Q) will improve cardiac dysfunction in old mice. Methods: 21-month-old C57Bl/6 mice were treated with D&amp;Q or vehicle via oral gavage on a bi-monthly basis for three months. Systolic and diastolic cardiac function were assessed using echocardiography. Expression of inflammatory and matrix metalloproteinase genes was assessed using quantitative polymerase chain reactions. Cardiac tissue morphology was assessed by histological analysis. Results: D&amp;Q treatment improved ejection fraction (EF) in old mice (60.3% vs. 64.5%, con vs. D&amp;Q, p = 0.0207, n=18). Global longitudinal strain was improved by D&amp;Q treatment (-13.99% vs. -17.03%, con vs. D&amp;Q, p=.0005, n=18). Measures of diastolic function were improved after D&amp;Q treatment (n=18 for all): E/E’ (27.60 vs. 20.08, con vs. D&amp;Q, p&lt;.0001), isovolumetric relaxation time (IVRT, 22.74ms vs. 14.99ms, con vs. D&amp;Q, p&lt;.0001), and reverse longitudinal strain rate (rLSR, 4.64 1/s vs. 13.41 1/s, con vs. D&amp;Q, p&lt;.0001). Expression of inflammatory and matrix metalloproteinase genes ( cd3e, foxp3, tnf- α, mcp-1, mmp9 ) was lower in hearts from D&amp;Q treated compared to control mice (p≤0.05). Extracellular matrix collagen expression was lower in cardiac tissue from D&amp;Q treated compared to control (p&lt;0.01). Conclusions: For the first time we report a significant improvement in diastolic function in aged mice when treated long term with the senolytic therapy dasatinib and quercetin. Measurements of systolic function also improved, but not to the same degree as observed for diastolic function. Overall, senolytic therapy with D&amp;Q represents an attractive option to explore for the treatment of diastolic heart failure in humans.

Association of the matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of coronavirus disease 2019 (COVID-19); implications of contribution for development of neurological symptoms in the COVID-19 patients.

Seemingly, the Matrix metalloproteinases (MMPs) play a role in the etiopathogenesis of coronavirus disease 2019 (COVID-19). Here in this study, we determined the association of MMP9 rs3918242, MMP3 rs3025058, and MMP2 rs243865 polymorphisms with the risk of COVID-19, especially in those with neurological syndrome (NS). We enrolled 500 patients with COVID-19 and 500 healthy individuals. To genotype the target SNPs, the Real-time allelic discrimination technique was used. To determine serum levels of MMPs, Enzyme-linked immunosorbent assay (ELISA) was exerted. The MMP9 gene rs3918242 and MMP3 gene rs3025058 SNP were significantly associated with increased COVID-19 risk and susceptibility to COVID-19 with NS. The serum level of MMP-9 and MMP-3 was significantly higher in COVID-19 cases compared with the healthy controls. Serum MMP-9 and MMP-3 levels were also higher in COVID-19 subjects with NS in comparison to the healthy controls. The polymorphisms in MMP genes were not associated with serum level of MMPs. MMP9 and MMP3 gene polymorphisms increases the susceptibility to COVID-19 as well as COVID-19 with neurologic syndrome, but they probably have no role in the regulation of serum MMP-9 and MMP-3 levels.

Matrix metalloproteinase gene mutations and bioinformatics of telocytes in hepatocellular carcinoma.

Telocytes (TCs) have crucial functions to promote the metastasis of hepatocellular carcinoma (HCC) by over-expressing matrix metalloproteinases (MMPs), but the mechanism by which TCs secrete MMPs in the genome is still unknown. We first cultured and isolated primary TCs from distinct liver cancer tissues and hepatic hemangioma surrounding tissues (Control group). Their whole exon genes were tested by Illumina HiSeq family of platforms and by high-throughput sequencing as well as variant mutations. Moreover, immunohistochemistry, Western blot, and quantitative reverse transcription-polymerase chain reactionassays were utilized to assess the expression of MMPs. The perniciousness of signal-nucleotide polymorphism (SNP) mutations of proteins were predicted by the Polyphen-2 database. Divergent expression and overall survival (OS) of MMPs was screened by StarBase-Pan Cancer plate; and MMPs associated signaling pathways were found by Kyoto Encyclopedia Genes andGenomes. The "competing endogenous RNA(ceRNA)" network was constructed by Cytoscape software. We found that 12 specific types of SNP mutations related to 5 types of MMPs occurred in TCs of liver malignant tumors as a potential result of MMP1, MMP9, and MMP17 overexpression. High levels of MMP1, MMP7, and MMP9 represented poor OS in HCC, and an interactive network of MMPs is shown. Allele shifts of C/T (rs20544) and G/C (rs2250889) in MMP9 were risk factors for TCs in HCC by the prediction of the Polyphen-2 Database. (MMP9(-3 C/T)) mutation might be a genetic mechanism of upregulating MMP9 in TCs.

Matrixmetalloproteinase-9 gene polymorphism (rs 17576) increases the risk of depressive symptoms in bipolar disorder.

Plasticity of neural synapses is known to be involved in the complications in bipolar disorder (BD) patients. Matrix metalloproteinases (MMPs) play a role in synaptic plasticity and memory. Even though elevated MMP-9 levels are reported in neuropsychiatric disorders, there is limited data about MMP-9 gene polymorphism in BD. The objectives of the study was to investigate genotype frequency and allele frequency of MMP-9 genetic variant (rs 17576) in BD and its association with disease severity. Eighty BD cases and 80 controls were recruited in the study. MMP-9 genotyping and allele frequency and plasma MMP-9 levels were analyzed in both the groups. Hamilton depression rating scale and Young's Mania Rating Scale (YMRS) were used to evaluate severity of BD. The genotype and minor allele (G allele) frequency were not significant between BD and controls. MMP-9 levels were significantly increased in BD patients with AG (P < 0.001) and GG (P = 0.022) genotypes compared to controls. BD patients with GG genotype (P = 0.038, OR: 3.26 (1.16-9.09), and G (mutant) allele (P = 0.013, OR 2.03(1.18-3.48) confer increased risk of depressive symptoms. MMP-9 was positively correlated with YMRS scale (r = 0.227, P = 0.043) in BD. MMP-9 gene polymorphism (rs 17576) is linked with depressive symptoms in BD.

Matrix Metalloproteinase Gene Polymorphisms Are Associated with Breast Cancer in the Caucasian Women of Russia.

We conducted this study to explore the association between matrix metalloproteinase (MMP) gene polymorphisms and breast cancer (BC) risk in the Caucasian women of Russia. In total, 358 affected (BC) and 746 unaffected (cancer-free) women were included in this case-control retrospective study. From BC-related genes in previous studies, ten single nucleotide polymorphisms (SNPs) in five MMP genes (MMP1, 2, 3, 8, 9) were genotyped. The BC risk was calculated by logistic regression (to evaluate the SNPs’ independent effects) and model-based multifactor dimensionality reduction (MB-MDR) (to identify SNP–SNP interactions) methods. The allelic variants’ distribution of c.836 A > G (rs17576) and c. 1721 C > G (rs2250889) MMP9 was significantly different between BC and cancer-free women: for G minor alleles, these SNPs manifested disorder protective effects (OR 0.82 and OR 0.67–0.71, respectively, pperm ≤ 0.035). Eleven haplotypes of six SNPs MMP9 were involved in BC risk (nine haplotypes) and protective (two haplotypes) effects. All 10 SNPs of the MMP genes examined were associated with BC within the 13 SNP–SNP interaction simulated models, with a pivotal role of the two-locus (rs17577 × rs3918242) MMP9 epistatic interaction (defined as 1.81% BC entropy within more than 60% of the genetic models). Under in silico bioinformatics, BC susceptibility MMP polymorphic loci are located in functionally active genome regions and impact genes expression and splicing “regulators” in the mammary gland. The biological pathways of BC MMP candidate genes are mainly realized due to metalloendopeptidase activity and extracellular matrix organization (structure, disassembly, metabolic process, etc.). In conclusion, our data show that MMP gene polymorphisms are related to BC susceptibility in the Caucasian women of Russia.

Gene polymorphisms of cyclin-dependent kinase inhibitor and matrix metalloproteinase-9 in Sudanese patients with esophageal squamous cell carcinoma.

The polymorphisms of the cyclin-dependent kinase inhibitor (CDKN1A) gene and matrix metalloproteinase-9 (MMP9) gene may increase one's susceptibility to malignancies. In this study, the association of the single nucleotide polymorphisms (SNPs) CDKN1A rs1059234 c.70C>T at the 3' untranslated region and MMP9 rs17576 (c.836A>G, p.Gln279Arg) with esophageal squamous cell carcinoma (ESCC) in Sudanese individuals were investigated. A case-control study involving age- and gender-matched groups were conducted in a cancer center in eastern Sudan (Gadarif) between April and October 2020. The case group consisted of ESCC patients, whereas the control group comprised healthy subjects. Polymerase chain reaction-restriction fragment length polymorphism was performed for the genotyping of the CDKN1A rs1059234 and MMP9 rs17576 SNPs. The genotyping results were confirmed by Sanger sequencing. The genotype distributions for CDKN1A rs1059234 and MMP9 rs17576 were in agreement with the Hardy-Weinberg equilibrium. The variant allele T in CDKN1 rs1059234 c.70C>T was significantly more prevalent in the ESCC patients than in the healthy controls [51.3% vs. 19.2%; OR=4.4; 95% CI (2.6-7.4); p < 0.001]. Moreover, in CDKN1A rs1059234, the genotype TC + TT [76.9% vs. 38.4%; OR=5.3; 95% CI (2.6-10.7); p < 0.001] was more frequent in the cases than in the controls, and it was significantly associated with ESCC risk. In MMP9 rs17576, the variant allele G was also significantly prevalent in the cases relative to the controls, and it was significantly associated with increased ESCC risk in the cases compared with the controls [27.5% vs. 1.9%; OR=19.4; 95%CI (5.8-64.1); p < 0.001]. Both genotypes containing the allele G (AG + GG) were the most common genotypes in the cases [48.7% vs. 3.8%; OR=23.7; 95%CI (6.8-81.7); p < 0.001], and they significantly increased the risk of ESCC. A significant increase in ESCC risk is associated with the SNPs CDKN1A rs1059234 and MMP9 rs17576.

The Modifying Effect of Obesity on the Association of Matrix Metalloproteinase Gene Polymorphisms with Breast Cancer Risk.

Objective: We investigated the possible modifying effect of obesity on the association of matrix metalloproteinase (MMP) gene polymorphisms with breast cancer (BC) risk. Methods: A total of 1104 women divided into two groups according to their body mass index (BMI): BMI ≥ 30 (119 BC, and 190 control) and BMI < 30 (239 BC, and 556 control) were genotyped for specially selected (according to their association with BC in the previous study) 10 single-nucleotide polymorphisms (SNP) of MMP1, 2, 3, 8, and 9 genes. Logistic regression association analysis was performed in each studied group of women (with/without obesity). Functional annotation of BC-correlated MMP polymorphic variants was analyzed by in silico bioinformatics. Results: We observed significant differences in the involvement of MMP SNPs in BC in obese and non-obese women. Polymorphic loci MMP9 (c.836 A > G (rs17576) and c. 1721 C > G (rs2250889)) were BC-protective factors in obese women (OR 0.71, allelic model, and OR 0.55, additive model, respectively). Genotypes TT MMP2 (c.-1306 C > T,rs243865) and AA MMP9 (c. 1331-163 G > A,rs3787268) determined BC susceptibility in non-obese women (OR 0.31, and OR 2.36, respectively). We found in silico substantial multidirectional influences on gene expression in adipose tissue BC-related polymorphic loci: BC risk allele A-rs3787268 in non-obese women is associated with low expression NEURL2, PLTP, RP3-337O18.9, SPATA25, and ZSWIM1, whereas BC risk allele A-rs17576 in obese women is associated with high expression in the same genes in visceral and/or subcutaneous adipose. Conclusions: our study indicated that obesity has a significant modifying effect on the association of MMP genes with BC risk in postmenopausal women.

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer.

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.

Tofacitinib Inhibits STAT Phosphorylation and Matrix Metalloproteinase-3, -9 and -13 Production by C28/I2 Human Juvenile Chondrocytes.

PurposeThis in vitro study was designed to determine the effect of the pan-Janus kinase inhibitor, Tofacitinib, on basal and interleukin-6 (IL-6)-induced signal transducers and activators of transcription (STAT) phosphorylation and matrix metalloproteinase (MMP) gene expression and MMP production by C28/I2 human chondrocytes.MethodsC28/I2 chondrocytes were grown to a confluent high-density and treated either with recombinant human IL-6 (rhIL-6; 10–20ng/mL) or maintained in the basal state for up to 60 min. MMP gene expression was determined using RT-PCR and MMP production by semi-quantitative immunohistochemistry. The effect of IL-6 with or without Tofacitinib on activation of STAT proteins was determined from quantitative Western blots.ResultsC28/I2 chondrocytes produced STAT1, STAT3 and STAT5AB which were phosphorylated (p) following treatment with rhIL-6 for 30 min. Tofacitinib (2.5nM–100nM) decreased rhIL-6-induced activation of STAT1, STAT3, and STAT5AB as well as decreasing the expression of MMP3 and MMP13 but not MMP9, MMP1 or MMP2. In addition, Tofacitinib (50nM) reduced the number of rhIL-6-induced MMP3-, and MMP13- antibody-positive C28/I2 chondrocytes. However, Tofacitinib did decrease the number of MMP9-antibody-positive C28/I2 chondrocytes.ConclusionTaken together, these data showed that Tofacitinib, a pan-JAK small molecule inhibitor employed for the medical therapy of rheumatoid arthritis was a potent inhibitor of rhIL-6-induced STAT phosphorylation that appeared to be coupled to the inhibition of MMP-3, -9 and -13 production by C28/I2 chondrocytes.