Degradation Of Extracellular Matrix Components Research Articles

(154) - Extracellular matrix mediated plasticity in neuropathic pain

In the nervous system, neurons and glial cells are embedded within an extracellular matrix (ECM), whose components not only provide structural support, but also regulate synapse formation and function, and modulate neuronal excitability. In the brain, ECM restricts synaptic and structural plasticity, and enzymatic digestion of ECM affects acquisition of memories, and promotes cognitive flexibility and extinction. In the pain pathway, matrix metalloproteinases (MMPs), the major ECM-digesting enzymes, are activated in neuropathic pain conditions to promote mechanical hypersensitivity; however, whether remodeling of spinal cord ECM contributes to pathological changes in dorsal horn nociceptive circuits and pain hypersensitivity remains unknown. We found that chronic inflammation and neuropathic pain lead to changes in the expression of ECM-related genes and to remodeling of the spinal ECM. To investigate the role of the ECM in restraining spinal plasticity, we injected chondroitinase ABC (chABC, an enzyme known to degrade ECM components) intrathecally before subjecting mice to Chronic Constriction Injury (CCI). Mice injected with chABC developed increased pain hypersensitivity as compared to that of vehicle-injected animals. Moreover, we found that Spared Nerve Injury (SNI) induces changes in spinal ECM chondroitin sulfate proteoglycans (CSPGs) such as Versican, Neurocan and Wisteria floribunda agglutinin (WFA)-binding proteins. In summary, our study demonstrates that peripheral nerve injury induces changes in the spinal ECM, suggesting a potential role of these modifications in the development of hypersensitivity.

Suitability assessment of baseline concentration of MMP3, TIMP3, HE4 and CA125 in the serum of patients with ovarian cancer

BackgroundMMP and TIMP play an important role in the degradation of extracellular matrix components which are essential for tumor growth, invasion and metastasis. Aim of this research was to assess MMP3 and TIMP3 as prognostic factors among patients with ovarian cancer.ResultsIt was found that high levels of output MMP3 correlated with shortened overall survival time of patients by 9.7 months. In addition, it has been shown that high concentrations of output MMP3 were significantly associated with a shorter disease free time in median concentrations implemented p = 0.0059. Statistically significant dependence has been shown between an average concentration of TIMP3 protein to the overall survival of patients. The higher output concentration of TIMP3, the longer patients’ survival by 8.9 month. In addition, it was found that high TIMP3 concentrations output were associated with a significantly longer disease free duration at a median concentrations p = 0.007.ConclusionPreliminary research shows that output levels of MMP3 and TIMP3 proteins correlate with overall survival of patients. In some cases also time free of illness.

Pioglitazone Alleviates Cardiac Fibrosis and Inhibits Endothelial to Mesenchymal Transition Induced by Pressure Overload

Background/Aims: Cardiac fibrosis, characterized by an unbalanced production and degradation of extracellular matrix components, is a common pathophysiology of multiple cardiovascular diseases. Recent studies suggested that endothelial to mesenchymal transition (EndMT) could be a source of activated fibroblasts and contribute to cardiac fibrosis. Here, the role of pioglitazone (PIO) in cardiac fibrosis and EndMT was elaborated. Methods: Male C57BL/6 mice were subjected to aortic banding (AB), which was used to construct a model of pressure overload-induced cardiac hypertrophy. PIO and GW9662 was given for 4 weeks to detect the effects of PIO on EndMT. Results: Our results showed PIO treatment attenuated cardiac hypertrophy, dysfunction and fibrosis response to pressure overload. Mechanistically, PIO suppressed the TGF-β/Smad signaling pathway activated by 4-week AB surgery. Moreover, PIO dramatically inhibited EndMT in vivo and in vitro stimulated by pressure overload or TGF-β. A selective antagonist of PPAR-γ, GW9662, neutralized the anti-fibrotic effect and abolished the inhibitory effect of EndMT during the treatment of PIO. Conclusion: Our data implied that PIO exerts an alleviative effect on cardiac fibrosis via inhibition of the TGF-β/Smad signaling pathway and EndMT by activating PPAR-γ.

The cysteinyl leukotriene receptor 1 (CysLT1R) antagonist montelukast suppresses matrix metalloproteinase-13 expression induced by lipopolysaccharide

Bacterial products such as LPS are critical factors responsible for bone destruction. MMP-13, a member of the matrix metalloproteinase family, plays a critical role in the proteolytic degradation of extracellular matrix components, which includes collagen fibrils in the bone matrix. Montelukast is a selective cysteinyl leukotrienes receptor 1 (cysLT1R) antagonist used clinically for the treatment of asthma, as it reduces eosinophilic inflammation in airways. This study aims to explore the role of montelukast in regulating MMP-13 expression induced by LPS in osteoblasts. Our results indicate that LPS stimulated cysLT1R expression in mouse MC3T3-E1 osteoblasts in a dose- and time-dependent manner. Notably, LPS-induced up-regulation of MMP-13 was ameliorated by treatment with montelukast in a dose-dependent manner. Furthermore, treatment with montelukast stimulated the expression of SOCS3, an inhibitor of MMP-13. Silencing of SOCS3 abolished the inhibitory effects of montelukast on MMP-13 expression. Mechanistically, we found that montelukast suppressed LPS-induced nuclear translocation of NF-κB p65 as well as NF-κB transcriptional activity by inhibiting the phosphorylation and degradation of IκBα. These data suggest that montelukast can modulate inflammatory events in bone diseases.

ShRNA-mediated downregulation of α-N-Acetylgalactosaminidase inhibits migration and invasion of cancer cell lines.

Objective(s):Extracellular matrix (ECM) is composed of many kinds of glycoproteins containing glycosaminoglycans (GAGs) moiety. The research was conducted based on the N-Acetylgalactosamine (GalNAc) degradation of ECM components by α-N-acetylgalactosaminidase (Nagalase) which facilitates migration and invasion of cancer cells. This study aims to investigate the effects of Naga-shRNA downregulation on migration and invasion of cancer cell lines.Materials and Methods:In this study, MCF-7 cell line (human mammary carcinoma cell line) and A2780 (human ovarian carcinoma cell line) were used. The level of normalized Naga expression and Nagalase protein were evaluated by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay/western blotting, respectively. Migration and invasion were determined using transwell assays, and statistical analysis was carried out by ANOVA test.Results:Response to transduction by shRNA compared to the control group, migrative and invasive properties of the transfected cells were significantly inhibited.Conclusion:These results indicate that Nagalase may have an important role in migration and invasion of cancer cells and can be considered as a candidate for further studies.

Gene Expression Profiling in Abdominal Aortic Aneurysms After Finite Element Rupture Risk Assessment

Purpose: To investigate the association between local biomechanical rupture risk calculations from finite element analysis (FEA) and whole-genome profiling of the abdominal aortic aneurysm (AAA) wall to determine if AAA wall regions with highest and lowest estimated rupture risk show different gene expression patterns. Methods: Six patients (mean age 74 years; all men) scheduled for open surgery to treat asymptomatic AAAs (mean diameter 55.2±3.5 mm) were recruited for the study. Rupture risk profiles were estimated by FEA from preoperative computed tomography angiography data. During surgery, AAA wall samples of ~10 mm2 were extracted from the lowest and highest rupture risk locations identified by the FEA. Twelve samples were processed for RNA extraction and subsequent whole genome expression profiling. Expression of single genes and of predefined gene groups were compared between vessel wall areas with highest and lowest predicted rupture risk. Results: Normalized datasets comprised 15,079 gene transcripts with expression above background. In biopsies with high rupture risk, upregulation of 18 and downregulation of 18 genes was detected when compared to the low-risk counterpart. Global analysis of predefined gene groups revealed expression differences in genes associated with extracellular matrix (ECM) degradation (p<0.001), matrix metalloproteinase activity (p<0.001), and chemokine signaling (p<0.001). Conclusion: Increased expression of genes involved in degrading ECM components was present in AAA wall regions with highest biomechanical stress, supporting the thesis of mechanotransduction. More experimental studies with cooperation of multicenter vascular biobanks are necessary to understand AAA etiologies and identify further parameters of FEA model complementation.

Sensitivity of Enzymatic Toxins from Corneal Isolate of Acanthamoeba Protozoan to Physicochemical Parameters.

Acanthamoeba is a free-living amoeba that causes severe corneal infection (Acanthamoeba keratitis) and produces a variety of extracellular enzymes, called exoproteome. Since physicochemical characters are suggested being associated with therapeutic profile and clinical severity of the infection, we investigated the physicochemical properties of proteolysis mediated by amoebic exoproteome. Corneal scraping was collected from a patient who showed typical symptoms of acute Acanthamoeba keratitis. Axenic amoeba was phylogenetically identified by 18S rDNA sequencing analysis. Effects of pH, temperature and diamidines on proteolysis mediated by exoproteome were assessed using zymography assays. Proteolytic enzymes were most active at pH 7.0 and 37°C. Calcium ions decreased enzymatic activity. The main components of amoebic exoproteome were characterized as serine proteases. We demonstrated for the first time that commercial antimicrobial diamidines used for Acanthamoeba keratitis therapy inhibit enzymatic activity of amoebic exoproteome. Results showed the thermostability of Acanthamoeba proteases, which suggest a long-term effect of these virulence factors at the central and peripheral cornea with possible role in degradation of extracellular matrix components. Our findings open new perspectives about the complementary and unreported properties of antimicrobial compounds of the diamidine class on the inhibition of enzymatic activity and presumptive control of amoebic infection in the cornea.

Non-coding RNA Contribution to Thoracic and Abdominal Aortic Aneurysm Disease Development and Progression.

Multiple research groups have started to uncover the complex genetic and epigenetic machinery necessary to maintain cardiovascular homeostasis. In particular, the key contribution of non-coding RNAs (ncRNAs) in regulating gene expression has recently received great attention. Aneurysms in varying locations of the aorta are defined as permanent dilations, predisposing to the fatal consequence of rupture. The characteristic pathology of an aneurysm is characterized by progressive vessel wall dilation, promoted by dying vascular smooth muscle cells and limited proliferation, as well as impaired synthesis and degradation of extracellular matrix components, which at least partially is the result of transmural inflammation and its disruptive effect on vessel wall homeostasis. Currently no conservative pharmacological approach exists that could slow down aneurysm progression and protect from the risk of acute rupture. In the recent past, several non-coding RNAs (mainly microRNAs) have been discovered as being involved in aneurysm progression throughout varying locations of the aorta. Exploring ncRNAs as key regulators and potential therapeutic targets by using antisense oligonucleotide strategies could open up promising opportunities for patients in the near future. Purpose of this current review is to summarize current findings and novel concepts of perspectivly utilizing ncRNAs for future therapeutic and biomarker applications.

Selective inhibition of matrix metalloproteinase-9 in CD4+ T-cells reduces clinical severity in a murine model of Multiple Sclerosis.

Abstract Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix components. Their functions are essential for normal physiological processes such as leukocyte trafficking, but their dysregulation is associated with various pathologies including Multiple Sclerosis (MS). During MS, CD4+ T-cells activated in the periphery penetrate the blood-brain barrier (BBB), recruit immune cells, initiate destruction of the myelin sheath, and cause axonal loss. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. In EAE, MMP-9 is required for penetration of the BBB and generation of auto-antigens. Recent studies have demonstrated that MMP-9 contributes to normal intracellular function of various cell types including antigen activated T-cells; however, the intracellular role of MMP-9 in immune cell activation during EAE pathogenesis is not known. In our studies, we demonstrate that the MMP-9 is important for homeostatic maintenance as well as a robust antigenic stimulation. Upon activation, CD4+ T-cells treated with an MMP-9 inhibitor demonstrate a reduced ability to enter cell cycle, proliferate, and produce cytokines. In addition, RNA-seq analysis highlight key proteins associated with the T-cell receptor signaling pathway that are impacted. Furthermore, treatment of EAE mice resulted in reduced clinical severity. This reduction is associated with a treatment regimen that starts on Day 7 as opposed to Day 0, suggesting that CD4+ T cells are more sensitive to the impact of MMP-9 inhibition compared to other immune cells. These results emphasize the importance of MMP-9 as a therapeutic target in CD4+ T-cell mediated autoimmune diseases.

CARDIOPROTECTIVE PROPERTIES OF PROGESTINES: INFLUENCE OF DROSPIRENONE ON MYOCARD IN EXPERIMENTAL HEART FAILURE

Aim. To assess the influence of synthetic progesterone — drospirenone, on remodeling of the left ventricle myocardium (LV) in ovariectomized (OE) female rats under circumstances of experimental heart failure (EHF). Material and methods. The study was done on 25 female Wistar rats, mass 260-300 g. Twenty animals (in 2 months after bilateral ovariectomy) underwent modeling of EHF by subcutaneous load of 0,1% mesaton solution for 14 days with following swimming to profound exhaustion. Four rats were removed on 14th day of EHF. Sixteen experimental animals with EHF were selected to 3 groups: 10 underwent 14 days subcutaneous load of drospirenon (Sigma-Aldrich, USA), dose 2 mg/kg (n=5) and 0,5 mg/kg (n=5), 6 were being loaded saline 0,2 mL daily. On 28th day the animals were removed from the experiment. With light microscopy method, immune cytochemistry, morphometry the LV myocardium was investigated. Results . In OE rodents on the 14th day of EHF there was clear and significant heteromorphism of contractile cardiomyocytes (CMC) with the signs of hypertrophy and dystrophy; increase of the volume density (VD) of stroma, reorganized extracellular matrix (EM), expression of metalloproteases-2,9 (MMP-2,9) and tissue inhibitor of metalloproteases-1 (TIMP-1), CMC with apoptosis. After remodeling of EHF at 28th day in myocardium there was further increase of CMC number with significantly changed morphology and tinctorial properties, degradation of EM components. In rats receiving 14 days drospirenon, regardless of dosage, there was regression of pathological changes, decrease of CMC hypertrophy grade, as the nuclei, decrease of CMC with the signs of apoptosis, and stabilized EM components. Conclusion. The cardioprotective properties of drospirenon are discussed, that even in minimal therapeutic concentrations facilitates structural and functional rehabilitation of myocardium under conditions of gonade hormones deficiency and EHF.

Matrix metalloproteinase and colorectal cancer

Matrix metalloproteinase (MMP) plays an important role in the degradation of extracellular matrix components, which is crucial for tumor growth, invasion and metastasis. As one with the largest relative molecular mass in MMP family, MMP-9 takes part in the generation and progression of colorectal cancer. Research shows that MMP-9 can be used for the early diagnosis of colorectal cancer. The expression levels of MMP-9 in tissue and plasma are negatively correlated with prognosis of the postoperative patients with colorectal cancer. In addition, targeted therapy drugs will be designed on the basis of MMP-9 expression increased in colorectal cancer. Key words: Matrix metalloproteinase 9; Colorectal neoplasms; Diagnosis; Prognosis; Therapy

Selective inhibition of matrix metalloproteinase-9 reduces clinical severity in a murine model of Multiple Sclerosis via a reduced immune response

Abstract Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix components. Their functions are essential for normal physiological processes such as wound healing, but their dysregulation is associated with various pathologies including Multiple Sclerosis (MS). During MS, CD4+ T-cells activated in the periphery penetrate the blood-brain barrier (BBB), recruit immune cells, initiate destruction of the myelin sheath, and cause axonal loss. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. In EAE, MMP-9 is required for penetration of the BBB and generation of auto-antigens. Recent studies have demonstrated that MMP-9 contributes to normal intracellular function of various cell types including antigen activated T-cells; however, the intracellular role of MMP-9 in immune cell activation during EAE pathogenesis is not known. In our in vitro studies of immune cells we assessed their response to mitogen following treatment with an MMP-9 inhibitor (MMP-9I). We demonstrated that the MMP-9 intracellular activity is important for homeostatic maintenance as well as a robust immune response. Our in vivo studies using MMP9I resulted in reduced disease severity and a reduction in key EAE hallmarks, weight loss and clinical score. Furthermore, proliferation of immune cells in the periphery following disease induction was reduced and the cellular infiltrates across the BBB. These results further emphasize the importance of MMP-9 as a therapeutic target in autoimmune diseases in addition to its well-established extracellular roles. Thus, it presents a two pronged approach to the therapeutic treatment of autoimmunity.

Proteins involved on TGF-β pathway are up-regulated during the acute phase of experimental Chagas disease

Studies developed by our group in the last years have shown the involvement of TGF-β in acute and chronic Chagas heart disease, with elevated plasma levels and activated TGF-β cell signaling pathway as remarkable features of patients in the advanced stages of this disease, when high levels of cardiac fibrosis is present. Imbalance in synthesis and degradation of extracellular matrix components is the basis of pathological fibrosis and TGF-β is considered as one of the key regulators of this process. In the present study, we investigated the activity of the TGF-β signaling pathway, including receptors and signaling proteins activation in the heart of animals experimentally infected with Trypanosoma cruzi during the period that mimics the acute phase of Chagas disease. We observed that T. cruzi—infected animals presented increased expression of TGF-β receptors. Overexpression of receptors was followed by an increased phosphorylation of Smad2/3, p38 and ERK. Furthermore, we correlated these activities with cellular factors involved in the fibrotic process induced by TGF-β. We observed that the expression of collagen I, fibronectin and CTGF were increased in the heart of infected animals on day 15 post-infection. Correlated with the increased TGF-β activity in the heart, we found that serum levels of total TGF-β were significantly higher during acute infection. Taken together, our data suggest that the commitment of the heart associates with increased activity of TGF-β pathway and expression of its main components. Our results, confirm the importance of this cytokine in the development and maintenance of cardiac damage caused by T. cruzi infection.

Expression of matrix metalloproteinases and their inhibitors in the internal carotid artery wall in pathological tortuosity

The principal morphological sign of fibromuscular dysplasia in pathological tortuosity (PT) of the internal carotid artery (ICA) is the fragmentation of elastic fibers that are degraded by matrix metalloproteinases 2 and 9 (MMP-2, MMP-9). Nevertheless, the role of MMPs and their inhibitors in the pathogenesis of ICA PT remains completely unexplored. to investigate the expression of elastin-degrading MMPs and their inhibitors in the wall of the ICA in PT by immunohistochemistry and confocal laser scanning microscopy. Immunohistochemical examination was made using antibodies to MMP-2, MMP-9 and their tissue inhibitors TIMP-1 and TIMP-2. MMP-9 and TIMP-1 levels were determined by confocal laser scanning microscopy. Immunohistochemical examination revealed a statistically significant predominance of high concentrations of MMP-2 and MMP-9 and a low level of their inhibitor TIMP-1 in ICA PT, while simultaneous obvious accumulation of both markers was most often identified in the control group (p<0.05). Analysis of MMP-2/TIMP-2 and MMP-9/TIMP-2 ratios showed the prevalence of the simultaneously high expression of both proteins in ICA PT and in the control group too. The similar data were also obtained by confocal microscopy: the control group showed elevated MMP-9 and TIMP-1 expressions and the ICA PT control displayed a high proteinase and low inhibitor levels (p<0.05). Elastic fiber fragmentation in ICA PT is due to imbalance between MMPs and their inhibitors; namely, the prevalence of MMP-2 and MMP-9 over their inhibitor TIMP-1, which leads to the degradation of extracellular matrix components, primarily elastin.

MMP8 Is Increased in Lesions and Blood of Acne Inversa Patients: A Potential Link to Skin Destruction and Metabolic Alterations

Acne inversa (AI; also designated as hidradenitis suppurativa) is a chronic inflammatory disease with still unknown pathogenesis that affects the intertriginous skin of perianal, inguinal, and axillary sites. It leads to painful nodules, abscesses, and fistulas with malodorous secretion and is frequently associated with metabolic alterations. Here, we demonstrate that one of the most highly upregulated molecules in AI lesions is matrix metalloproteinase 8 (MMP8), an enzyme specialized in the degradation of extracellular matrix components and the HDL component apolipoprotein A-I. Granulocytes, which were present in AI lesions, secreted high amounts of MMP8 especially after TNF-α stimulation. Furthermore, activated fibroblasts but not keratinocytes were found to express MMP8. The high lesional MMP8 levels were accompanied by elevated blood levels that positively correlated with TNF-α blood levels and disease severity assessed by Sartorius score, especially with the number of regions with inflammatory nodules/abscesses and fistulas. Additionally, we found a negative correlation between blood MMP8 and HDL-cholesterol levels, suggesting a contributory role of MMP8 in metabolic alterations in AI. In summary, we demonstrate elevated MMP8 levels in AI lesions, suggest their role in skin destruction and metabolic alterations, and recommend the use of MMP8 as blood biomarker for AI disease activity assessment.

Serum matrix metalloproteinase 9 (MMP9) as a biochemical marker for wasting marmoset syndrome.

Use of the common marmoset (Callithrix jacchus) as a non-human primate experimental animal has increased in recent years. Although wasting marmoset syndrome (WMS) is one of the biggest problems in captive marmoset colonies, the molecular mechanisms, biochemical markers for accurate diagnosis and a reliable treatment remain unknown. In this study, as a first step to finding biochemical marker(s) for the accurate diagnosis of WMS, we conducted blood cell counts, including hematocrit, hemoglobin and platelets, and examined serum chemistry values, including albumin, calcium and levels of serum matrix metalloproteinase 9 (MMP9), using a colony of marmosets with and without weight loss. MMP9 is thought to be an enzyme responsible for the degradation of extracellular matrix components and participates in the pathogenesis of inflammatory conditions, such as human and murine inflammatory bowel disease, which, like WMS, are characterized histologically by inflammatory cell infiltrations in the intestines. The values of hematocrit and hemoglobin and levels of serum albumin and calcium in the WMS group were significantly decreased versus the control group. The platelet values and serum MMP9 concentrations were increased significantly in the WMS group compared with the control group. MMP9 could be a new and useful marker for the diagnosis of WMS in addition to hematocrit, hemoglobin, serum albumin and calcium. Our results also indicate that MMP9 could be a useful molecular candidate for treatment.

The role of matrix metalloproteinases in glaucoma pathogenesis

Matrix metalloproteinases belong to an enzyme family, which assure a proteolysis of practically all components of the extracellular matrix of connective tissues in normal and pathological conditions. At physiological conditions, there are evidences on the impact of this enzyme group in the embryogenesis, morphogenesis, angiogenesis, and tissue involution. The activity impairment of matrix metalloproteinases and of their specific inhibitors leads to the biosynthesis misbalance and to the degradation of extracellular matrix components; it plays a role in the development of such diseases as diabetes mellitus, rheumatoid arthritis, and arteriosclerosis. Laboratory tests and clinical investigation results confirm the role of these enzymes in tissue remodeling of different eyeball structures in glaucoma (in particular, of the trabecular meshwork and the optic disc); it leads to intraocular fluid outflow impairment and to the glaucomatous optic neuropathy development. In the review, the analysis of clinical and experimental studies is performed that are dedicated to the investigation of matrix metalloproteinases role in the pathogenesis of different glaucoma types, of the possibility to use them as biomarkers, as well as therapeutic action targets in this disease.

DNA Methylation of MMP9 Is Associated with High Levels of MMP-9 Messenger RNA in Periapical Inflammatory Lesions

IntroductionMatrix metalloproteinases (MMPs) are the major class of enzymes responsible for degradation of extracellular matrix components and participate in the pathogenesis of periapical inflammatory lesions. MMP expression may be regulated by DNA methylation. The purpose of the present investigation was to analyze the expression of MMP2 and MMP9 in periapical granulomas and radicular cysts and to test the hypothesis that, in these lesions, their transcription may be modulated by DNA methylation. MethodsMethylation-specific polymerase chain reaction was used to evaluate the DNA methylation pattern of the MMP2 gene in 13 fresh periapical granuloma samples and 10 fresh radicular cyst samples. Restriction enzyme digestion was used to assess methylation of the MMP9 gene in 12 fresh periapical granuloma samples and 10 fresh radicular cyst samples. MMP2 and MMP9 messenger RNA transcript levels were measured by quantitative real-time polymerase chain reaction. ResultsAll periapical lesions and healthy mucosa samples showed partial methylation of the MMP2 gene; however, periapical granulomas showed higher MMP2 mRNA expression levels than healthy mucosa (P = .014). A higher unmethylated profile of the MMP9 gene was found in periapical granulomas and radicular cysts compared with healthy mucosa. In addition, higher MMP9 mRNA expression was observed in the periapical lesions compared with healthy tissues. ConclusionsThe present study suggests that the unmethylated status of the MMP9 gene in periapical lesions may explain the observed up-regulation of messenger RNA transcription in these lesions.

Emetine inhibits migration and invasion of human non-small-cell lung cancer cells via regulation of ERK and p38 signaling pathways

Emetine is a natural compound originated from ipecac roots. It was commonly used as anti-protozoal and vomiting agent. The apoptosis-inducing effect of emetine makes it considered as a potential anti-cancer agent for various human cancers. Here in this study, we report that emetine inhibits migration and invasion of human non-small-cell lung cancer (NSCLC) cells. Modulation of three major mitogen-activated protein kinases (MAPKs), ERK, p38 and JNK, is well known to be involved in regulation of matrix metalloproteinases (MMPs), which are essential in tissue remodeling and extracellular matrix (ECM) degradation, for cancer cells to spread out from the origin of tumorigenesis. Emetine regulates two major MAPKs, p38 and ERK. Differential inhibition/stimulation of ERK and p38 induced differential suppressions of β-catenin and c-myc transcription factors. This leads to the selective down-regulation of MMP-2 and MMP-9, two major gelatinases which can degrade ECM components, and RECK, a negative regulator of MMP-9.

Matrix metalloproteinase-2 -1306 C>T gene polymorphism is associated with reduced risk of cancer: a meta-analysis.

Matrix metalloproteinase-2 (MMP2) is an endopeptidase, mainly responsible for degradation of extracellular matrix components, which plays an important role in cancer disease. A single nucleotide polymorphism (SNP) at -1306 disrupts a Sp1-type promoter site. The results from the published studies on the association between MMP2 -1306 C>T polymorphism and cancer risk are contradictory and inconclusive. In the present study, a meta-analysis was therefore performed to evaluate the strength of any association between the MMP2 -1306 C>T polymorphism and risk of cancer. We searched all eligible studies published on association between MMP2 -1306 C>T polymorphism and cancer risk in PubMed (Medline), EMBASE and Google Scholar online web databases until December 2013. Genotype distribution data were collected to calculate the pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) to examine the strength of the association. A total of 8,590 cancer cases and 9,601 controls were included from twenty nine eligible case control studies. Overall pooled analysis suggested significantly reduced risk associated with heterozygous genotype (CT vs CC: OR=0.758, 95%CI=0.637 to 0.902, p=0.002) and dominant model (TT+CT vs CC: OR=0.816, 95%CI=0.678 to 0.982, p=0.032) genetic models. However, allelic (T vs C: OR=0.882, 95%CI=0.738 to 1.055, p=0.169), homozygous (TT vs CC: OR=1.185, 95%CI=0.825 to 1.700, p=0.358) and recessive (TT vs CC+CT: OR=1.268, 95%CI=0.897 to 1.793, p=0.179) models did not show any risk. No evidence of publication bias was detected during the analysis. The results of present meta-analysis suggest that the MMP2 -1306 C>T polymorphism is significantly associated with reduced risk of cancer. However, further studies with consideration of different populations will be required to evaluate this relationship in more detail.