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EXPRESSION OF MATRIX METALLOPROTEINASE MMP-2 AND ITS TISSUE INHIBITOR TIMP-2 IN INTRAORAL PLEOMORPHIC ADENOMA AND ADENOID CYSTIC CARCINOMA
Natheer Hashim AL-Rawi,Muthanna Al-Samarai,Sausan Al-Kawas,Ahlam H. Majeed
Journal of International Dental and Medical Research , 2011,
Abstract: Matrix metalloproteinases (MMPs) are proteolytic enzymes that are capable of degrading different substrates within extracellular matrix (ECM), and are believed to be crucial for tumor invasion and metastasis. Tissue inhibitors of MMP (TIMPs) can inhibit the action of MMPs The aim of this study was to analyze protein expression of MMP-2 and TIMP-2 in intraoral pleomorphic adenoma (PLA) and adenoid cystic carcinoma (ACC). A total of 35 formalin-fixed paraffin-embedded specimens comprising 19 PLA and 16 ACC were utilized in this study. A standard immunohistochemical technique was used to determine the expression levels of MMP-2 and TIMP-2 proteins. Sections were assessed semi quantitatively .Staining was scored as 0 (< 1% positive tumor staining), 1+ (< 25% positive tumor cells), 2+ (20-50% positive tumor cells) and 3+ (> 50% positive tumor cells). For statistical analysis, tumors were divided into two groups, low expressors ( 0-1+) and high expressors (2-3+). PLA showed higher TIMP-2 expression than ACC (p<0.05). No significant difference was observed between PLA and ACC regarding MMP-2 expression. MMP-2 and TIMP-2 expressed mainly in the cytoplasm of epithelial/ myoepithelial components of PLA and neoplastic epithelial cells of ACC. Myoepithelial cells may be the primary source of gelatinases in PLA and the down regulation of TIMP-2 expression in ACC might be responsible for metastasis and recurrence. The ratio value of MMP-2/TIMP-2 is valuable parameter to demonstrate the ECM degradation/ deposition imbalance.
Associations among serum concentrations of interleukin-18, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and METAVIR fibrosis score in patients with chronic hepatitis
Olusi S, Abdeen S, George S
International Journal of Interferon, Cytokine and Mediator Research , 2012, DOI: http://dx.doi.org/10.2147/IJICMR.S28976
Abstract: ssociations among serum concentrations of interleukin-18, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and METAVIR fibrosis score in patients with chronic hepatitis Original Research (1440) Total Article Views Authors: Olusi S, Abdeen S, George S Published Date March 2012 Volume 2012:4 Pages 17 - 24 DOI: http://dx.doi.org/10.2147/IJICMR.S28976 Received: 07 December 2011 Accepted: 31 January 2012 Published: 13 March 2012 Samuel Olusi, Suad Abdeen, Sunila George Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait Abstract: During fibrogenesis, the quantity, proportion, and composition of matrix proteins in the liver change due to the activation of hepatic stellate cells (HSCs) resulting in excessive accumulation of fibrous tissue. The exact mechanisms of these changes are not fully known. In this study, we postulated that IL-18 may upregulate matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-1) in such proportions that will encourage fibrogenesis. To test this hypothesis we estimated the serum concentrations of IL-18, MMP-2, TIMP-1 in 56 patients with chronic hepatitis C virus (HCV), 28 patients with hepatitis B virus (HBV), 16 patients with non-alcoholic steatohepatitis (NASH) and 100 healthy controls using commercially available ELISA kits. The METAVIR activity and fibrosis scores of the liver biopsies from the patients were determined histologically. We found that IL-18 concentrations were significantly higher among HCV, HBV, and NASH patients than in healthy controls. We also found that IL-18 increased progressively from patients with no fibrosis (397.46 ± 73.54 pg/mL) to patients with cirrhosis (1384.11 ± 526.60 pg/mL). Although IL-18 is associated with minimal production of MMP-2 throughout the period of fibrosis from 199.48 ± 18.62 ng/mL at F0 to 225.25 ± 14.75 ng/mL at F4, it is associated with two-fold increase of TIMP-1 from 225.25 ± 14.75 ng/mL to 500.77 ± 30.50 ng/mL. We suggested that the high concentration of TIMP-1 inhibits the relatively low concentration of MMP-2 thus promoting the continuous deposition of collagen fibers in the liver. We concluded that IL-18 and TIMP-1 may be more important than MMP-2 in hepatic fibrogenesis.
Associations among serum concentrations of interleukin-18, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1) and METAVIR fibrosis score in patients with chronic hepatitis  [cached]
Olusi S,Abdeen S,George S
International Journal of Interferon, Cytokine and Mediator Research , 2012,
Abstract: Samuel Olusi, Suad Abdeen, Sunila GeorgeDepartment of Pathology, Faculty of Medicine, Kuwait University, KuwaitAbstract: During fibrogenesis, the quantity, proportion, and composition of matrix proteins in the liver change due to the activation of hepatic stellate cells (HSCs) resulting in excessive accumulation of fibrous tissue. The exact mechanisms of these changes are not fully known. In this study, we postulated that IL-18 may upregulate matrix metalloproteinase-2 (MMP-2) and its tissue inhibitor (TIMP-1) in such proportions that will encourage fibrogenesis. To test this hypothesis we estimated the serum concentrations of IL-18, MMP-2, TIMP-1 in 56 patients with chronic hepatitis C virus (HCV), 28 patients with hepatitis B virus (HBV), 16 patients with non-alcoholic steatohepatitis (NASH) and 100 healthy controls using commercially available ELISA kits. The METAVIR activity and fibrosis scores of the liver biopsies from the patients were determined histologically. We found that IL-18 concentrations were significantly higher among HCV, HBV, and NASH patients than in healthy controls. We also found that IL-18 increased progressively from patients with no fibrosis (397.46 ± 73.54 pg/mL) to patients with cirrhosis (1384.11 ± 526.60 pg/mL). Although IL-18 is associated with minimal production of MMP-2 throughout the period of fibrosis from 199.48 ± 18.62 ng/mL at F0 to 225.25 ± 14.75 ng/mL at F4, it is associated with two-fold increase of TIMP-1 from 225.25 ± 14.75 ng/mL to 500.77 ± 30.50 ng/mL. We suggested that the high concentration of TIMP-1 inhibits the relatively low concentration of MMP-2 thus promoting the continuous deposition of collagen fibers in the liver. We concluded that IL-18 and TIMP-1 may be more important than MMP-2 in hepatic fibrogenesis.Keywords: IL-18, MMP-2, TIMP-1, liver fibrosis
Levels of Circulating TIMP-2 and MMP2-TIMP2 Complex Are Decreased in Squamous Cervical Carcinoma  [PDF]
Talvensaari-Mattila Anne,Turpeenniemi-Hujanen Taina
Obstetrics and Gynecology International , 2010, DOI: 10.1155/2010/179351
Abstract: Background. The role of matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) in matrix degradation and metastasis has been described in various tumors. Their action is inhibited by their natural tissue inhibitor molecules TIMP-1 and -2. Methods. The study population consisted of 12 squamous cervical carcinoma patients and 27 healthy volunteer control patients. MMP-9, MMP-2-TIMP-2 complex, TIMP-1, and TIMP-2 were analyzed from serum samples using enzyme-linked immunoassay (ELISA). Results. The mean levels of serum TIMP-2 and of MMP-2-TIMP-2 complex were higher in healthy controls compared to patients with a malignant tumor. Serum TIMP-2 values decreased significantly from healthy controls (median 323? g/l, range 305–342? g/l) to malignant (median 136? g/l, range?120–151? g/l) squamous cervical carcinoma patients . Also, serum proMMP2-TIMP2 complex values decreased from control patients to squamous cervical carcinoma patients . Conclusion. This paper shows that the levels of circulating TIMP-2 and that of MMP-2-TIMP-2 complex are lower in squamous cervical carcinoma patients than in healthy women. 1. Introduction Cervical cancer is the second most common malignant disease among women worldwide [1]. However, its incidence and mortality rates have been decreasing in many highly developed countries, for example, the Nordic countries, mainly due to organized Pap smear screening [2]. Members of the matrix metalloproteinase (MMP) family have the ability to degrade macromolecules of the extracellular matrix, and they are responsible for tumor invasion and infiltration. They are a family of zinc and calcium-dependent proteinases, and they are secreted in the proenzyme form [3]. Besides their role in tumor invasion and metastasis, MMPs are involved in various physiological connective tissue remodeling processes, such as ovulation and wound healing [4]. Matrix metalloproteinases form an enzyme family that takes part in virtually all events of extracellular matrix remodeling and turnover. Cancer cells capable of producing these enzymes, especially of gelatinases MMP-2 and -9, have been shown to have increased invasion potential in several malignancies [5, 6]. Their action is inhibited by their natural tissue inhibitor molecules TIMP-1 and -2. There are no previous studies on circulating metalloproteinases and squamous cervical carcinoma. The aim of this paper was to evaluate the levels of circulating metalloproteinases and their inhibitors in squamous cervical carcinoma patients and healthy women. 2. Materials and Methods The patient material consisted of 12 early-stage
Interleukin 17A Promotes Gastric Cancer Invasiveness via NF-κB Mediated Matrix Metalloproteinases 2 and 9 Expression  [PDF]
Yidong Wang, Hong Wu, Xiaoling Wu, Zhuoqiong Bian, Qing Gao
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096678
Abstract: Interleukin 17A (IL-17A), as a pro-inflammatory cytokine, is involved in pathology of inflammatory diseases and tumor microenvironment. The aim of this study is to investigate the effect of IL-17A on the invasiveness of gastric cancer (GC). In the study, we found that IL-17A could promote the migration and invasion of GC cells. Furthermore, after treated with IL-17A, the expressions and activities of matrix metalloproteinase 2 (MMP-2) and MMP-9 were upregulated, while the expressions of TIMP-1 and TIMP-2 were downregulated. Moreover, the nuclear/overall fractions of p65 and p50 were dramatically elevated by IL-17A. Pretreatment with helenalin, a nuclear factor-κB (NF-κB) inhibitor, was proved to abolish the promoting effect of IL-17A on the invasion ability of GC cells and upregulation of MMP-2 and MMP-9. In conclusion, our findings illustrated that IL-17A could promote the invasion of GC cells by activating NF-κB pathway, and subsequently upregulating the expression of MMP-2 and MMP-9. These results may lead to the identification of new diagnostic markers and therapeutic targets of GC.
Matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in the diagnosis of colorectal adenoma and cancer patients.  [cached]
Magdalena Groblewska,Barbara Mroczko,Mariusz Gryko,Bogus?aw K?dra
Folia Histochemica et Cytobiologica , 2011, DOI: 10.5603/4175
Abstract: The aim of the study was to assess the importance of the measurement of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC) in relation to clinicopathological features of tumor and patients' survival. Additionally, we determined serum MMP-2 and TIMP-2 in colorectal adenoma (CA) patients and healthy controls and compared them with tumor markers, CEA and CA 19-9. The serum levels of MMP-2 and TIMP-2 in 91 CRC patients, 28 CA subjects and 91 healthy controls were determined by ELISA method, but concentrations of CEA and CA 19-9 using MEIA method. Nonparametric statistical analyses were used. Serum levels of MMP-2 and TIMP-2 were significantly lower in CRC patients than in healthy subjects and decreased with tumor stage. Additionally, MMP-2 concentrations were significantly lower in patients with CRC than in CA group. Diagnostic sensitivity of TIMP-2 (59%) was the highest among biomarkers tested and increased in combined use with CEA (79%). Moreover, the area under ROC curve (AUC) of TIMP-2 was larger than AUC of MMP-2 in differentiation between CRC and healthy subjects, but lower than AUC of matrix metalloproteinase 2 in differentiation between colorectal cancer and adenoma. Our findings suggest clinical usefulness of TIMP-2 as a biomarker in the diagnosis of CRC, especially in combination with CEA. However, further investigation is necessary.
Matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases 2 in the diagnosis of colorectal adenoma and cancer patients  [PDF]
Magdalena Groblewska,Barbara Mroczko,Mariusz Gryko,Boguslaw K?dra
Folia Histochemica et Cytobiologica , 2010,
Abstract: The aim of the study was to assess the importance of the measurement of matrix metalloproteinase 2 (MMP-2)and tissue inhibitor of matrix metalloproteinases 2 (TIMP-2) in patients with colorectal cancer (CRC) in relation to clinicopathologicalfeatures of tumor and patients' survival. Additionally, we determined serum MMP-2 and TIMP-2 in colorectaladenoma (CA) patients and healthy controls and compared them with tumor markers, CEA and CA 19-9. The serum levelsof MMP-2 and TIMP-2 in 91 CRC patients, 28 CA subjects and 91 healthy controls were determined by ELISA method, butconcentrations of CEA and CA 19-9 using MEIA method. Nonparametric statistical analyses were used. Serum levels ofMMP-2 and TIMP-2 were significantly lower in CRC patients than in healthy subjects and decreased with tumor stage.Additionally, MMP-2 concentrations were significantly lower in patients with CRC than in CA group. Diagnostic sensitivityof TIMP-2 (59%) was the highest among biomarkers tested and increased in combined use with CEA (79%). Moreover,the area under ROC curve (AUC) of TIMP-2 was larger than AUC of MMP-2 in differentiation between CRC and healthysubjects, but lower than AUC of matrix metalloproteinase 2 in differentiation between colorectal cancer and adenoma. Ourfindings suggest clinical usefulness of TIMP-2 as a biomarker in the diagnosis of CRC, especially in combination with CEA.However, further investigation is necessary.
Matrix Metalloproteinase-10/TIMP-2 Structure and Analyses Define Conserved Core Interactions and Diverse Exosite Interactions in MMP/TIMP Complexes  [PDF]
Jyotica Batra, Alexei S. Soares, Christine Mehner, Evette S. Radisky
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075836
Abstract: Matrix metalloproteinases (MMPs) play central roles in vertebrate tissue development, remodeling, and repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) regulate proteolytic activity by binding tightly to the MMP active site. While each of the four TIMPs can inhibit most MMPs, binding data reveal tremendous heterogeneity in affinities of different TIMP/MMP pairs, and the structural features that differentiate stronger from weaker complexes are poorly understood. Here we report the crystal structure of the comparatively weakly bound human MMP-10/TIMP-2 complex at 2.1 ? resolution. Comparison with previously reported structures of MMP-3/TIMP-1, MT1-MMP/TIMP-2, MMP-13/TIMP-2, and MMP-10/TIMP-1 complexes offers insights into the structural basis of binding selectivity. Our analyses identify a group of highly conserved contacts at the heart of MMP/TIMP complexes that define the conserved mechanism of inhibition, as well as a second category of diverse adventitious contacts at the periphery of the interfaces. The AB loop of the TIMP N-terminal domain and the contact loops of the TIMP C-terminal domain form highly variable peripheral contacts that can be considered as separate exosite interactions. In some complexes these exosite contacts are extensive, while in other complexes the AB loop or C-terminal domain contacts are greatly reduced and appear to contribute little to complex stability. Our data suggest that exosite interactions can enhance MMP/TIMP binding, although in the relatively weakly bound MMP-10/TIMP-2 complex they are not well optimized to do so. Formation of highly variable exosite interactions may provide a general mechanism by which TIMPs are fine-tuned for distinct regulatory roles in biology.
Feature changes of MMP-2/9 activities and TIMP-1/2 protein expressions during the progression of pulmonary fibrosis in rats  [cached]
Shan-Zhong TAN,Cheng-Hai LIU
Zhong Xi Yi Jie He Xue Bao , 2006,
Abstract: Objective: To investigate the dynamic trends of activities of matrix metalloproteinase (MMP)-2/9 and protein expressions of their inhibitors-tissue inhibitor of matrix metalloproteinase (TIMP)-1/2 during the progression of pulmonary fibrosis in rats so as to get insight of the roles played by MMP-2 /9 in lung injury and fibrogenesis. Methods: Forty-eight SD rats were randomly divided into normal control group (n=18) and bleomycin (BLM)-treated group (n=30). The pulmonary fibrosis was induced by intratracheal injection of BLM once. At the consecutive time of 1 day, 3 days, 1 week, 2, 3, and 4 weeks after intoxication, the lung-to-body weight ratio was calculated and the inflammation and collagen deposition in lung tissue were checked by HE and Masson stainings respectively. Meanwhile, the content of hypdroxyproline (Hyp) in lung tissue was assayed with Jamall’s method, the protein expressions of MMP-2/9, TIMP-1/2 were examined by Western blotting, and the activities of MMP-2/9 were detected by gelatin zymography. Results: The histopathological changes in lung tissue in the BLM-treated group from 1 day to 2 weeks after intoxication presented local lesions, broadened alveolar wall and septum, infiltration with lots of inflammatory cells and few of fibroblasts inside alveolar space and septum. At this early stage in the BLM-treated group, the lung-to-body weight ratio was increased significantly, the protein expressions and activities of MMP-2/9 were obviously increased especially for activity of active MMP-2, and the protein expressions of TIMP-1/2 were also increased gradually, as compared with those in the normal control group. From 3 to 4 weeks after intoxication in the BLM-treated group, the alveolar structure was damaged, parts of the alveolar space collapsed and replaced by collagens and fibroblasts, and the alveolar wall and septum obviously widened with remarkable fibrotic characteristics, as compared with those in the normal control group. Meanwhile, the lung-to-body weight ratio and the activities of MMP-2/9 were decreased in the BLM-treated group as compared with those in the same group at 2 weeks after intoxication, but the content of Hyp and the protein expressions of TIMP-1/2 were both increased dramatically, especially at 4 weeks after intoxication. Conclusions: During the lung fibrogenesis induced by BLM in rats, the alveolar inflammation is the most important alteration with enhanced MMP-2/9 activities in the early stage. While in the late stage, the main change is displayed as pulmonary fibrosis, characterized by increased TIMP-1/2 and de
NDRG2 Ameliorates Hepatic Fibrosis by Inhibiting the TGF-β1/Smad Pathway and Altering the MMP2/TIMP2 Ratio in Rats  [PDF]
Jiandong Yang,Jin Zheng,Lin Wu,Ming Shi,Hongtao Zhang,Xing Wang,Ning Xia,Desheng Wang,Xinping Liu,Libo Yao,Yan Li,Kefeng Dou
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0027710
Abstract: Liver fibrosis is a worldwide clinical issue. It has been well established that activated hepatic stellate cells (HSCs) are responsible for excessive extracellular matrix (ECM) deposition in chronically damaged livers. The identification of key elements that control HSCs activation will help to further our understanding of liver fibrosis and improve the outcome of clinical treatment. This study demonstrates that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of liver fibrosis as NDRG2 mRNA and protein levels were reduced during HSCs activation. In addition, enhanced NDRG2 expression reduced Smad3 transcription and phosphorylation, which inhibited HSCs activation by blocking the TGF-β1 signal. Moreover, NDRG2 contributed to an increase in the ratio of matrix metalloproteinase 2 (MMP2) to tissue inhibitor of matrix metalloproteinase 2 (TIMP2), which may facilitate the degradation of the ECM. In dimethylnitrosamine (DMN)-induced fibrotic rat livers, adenovirus-mediated NDRG2 overexpression resulted in decreased ECM deposition and improved liver function compared with controls. In conclusion, the present findings indicate that the modulation of NDRG2 is a promising strategy for the treatment of liver fibrosis.
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