Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship to CXCR4 and its ligand CXCL12 in ccRCC is unclear. By using reverse transcription PCR, immunofluorescence and immunohistochemistry, strong mRNA and protein expression of CXCR4, CXCL12, MMP2, MMP9 and MMP inhibitors TIMP1 and TIMP2 was found in VHL-null 786-O ccRCC cells. Loss of CXCR4/CXCL12 expression after restoration of VHL function in these cells was accompanied by a significant reduction of MMP2 and MMP9 expression, whereas neither TIMP1 nor TIMP2 expression was affected. Using real-time PCR analysis, higher MMP2 (p = 0.0134) and MMP9 (p = 0.067) mRNA expression levels were detected in primary ccRCC with strong CXCR4 compared to cases with weak CXCR4 expression. There was no association between CXCR4 and TIMP1 or TIMP2 mRNA expression. MMP2 protein expression data obtained by immunohistochemistry on a tissue microarray uncovered positive cytoplasmic staining in 290/380 (76%) primary ccRCCs. Co-expression of CXCR4 and MMP2 was found in 282 of these tumours (74%). Our in vitro and in vivo data strongly indicate that pVHL coordinately regulates expression of metastasis-associated genes CXCR4/CXCL12 and MMP2/MMP9 but the exact molecular mechanism of this regulation remains to be determined. Co-expression of CXCR4 and CXCL12, as demonstrated in VHL-null 786-O cells, might enable ccRCC progression and metastatic dissemination by autocrine receptor stimulation, even in the absence of exogenous CXCL12.
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PMID:pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma. 1818 28

Remodeling of the pulmonary artery is a major feature of pulmonary artery hypertension, and CPU86017, a derivative of berberine, is known to effectively alleviate hypoxic pulmonary hypertension (HPH). CPU86017 is a racemate, possessing two chiral centers: 7N and 13aC. We have compared the effects of four CPU86017 isomers, SS [(+)-7S, 13aS-CPU86017], SR [(-)-7S, 13aR-CPU86017], RR [(-)-7R, 13aR-CPU86017] and RS [(+)-7R, 13aS-CPU86017], on HPH. Sprague-Dawley rats were exposed to hypoxic conditions (10 +/- 0.5% O2 for 8 h per day) for 4 weeks and treated with CPU86017, SS, SR, RR or RS (4 mg/kg, subcutaneously) from day 15 to 28. After 4 weeks of exposure to hypoxia, remodeling of the right ventricle and the small pulmonary arteries (<150 microm) was very pronounced, and extra-cellular matrix (ECM) had been excessively produced in association with abnormal mRNA and protein expression of matrix metalloproteinase 9 (MMP9) and mRNA of tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1, TIMP2). Expression of endothelin receptor A was upregulated, while that connexin 40 was downregulated. The administration of CPU86017 and its four isomers attenuated the changes, with the isomer RS exhibiting the most favorable effect on HPH rats. We propose that an activated endothelin pathway associated with an unbalanced MMP-TIMP system may contribute to the over-accumulation of ECM and the remodeling of the pulmonary arterioles in HPH. CPU86017 and its four isomers attenuate ECM accumulation and vascular remodeling by normalizing both the MMP-TIMP system and the ET system. The RS isomer is superior to the racemate CPU86017 in attenuating HPH.
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PMID:CPU86017 and its isomers improve hypoxic pulmonary hypertension by attenuating increased ETA receptor expression and extracellular matrix accumulation. 1854 32

Successful pregnancy depends on the precise regulation of extravillous trophoblast (EVT) invasion into the uterine decidua, primarily by decidua-derived factors. In humans, during early pregnancy interleukin 11 (IL11) is maximally expressed in the decidua, with its receptor, IL11 receptor alpha (IL11RA), also identified on invasive EVTs in vivo. Although a role for IL11 in EVT migration has been established, whether it also plays a role in regulating EVT invasion is unknown. We investigated whether IL11 influences human EVT invasion and the signaling pathways and underlying mechanisms that may be involved, using the HTR-8/SVneo immortalized EVT cell line and primary EVTs as models for EVTs. Interleukin 11 (100 ng/ml) significantly inhibited invasion of EVT cells by 40% to 60% (P < 0.001). This effect was abolished by inhibitors of signal transducer and activator of transcription 3 (STAT3) but not of mitogen-activated protein kinase (MAPK) pathways. Interleukin 11 (100 ng/ml) had no effect on matrix metallopeptidases 2 and 9 (MMP2 and MMP9), tissue inhibitors of MMP (TIMP1, TIMP2, and TIMP3), plasminogen activator urokinase (PLAU), plasminogen activator urokinase receptor (PLAUR), and serpin peptidase inhibitors 1 and 2 (SERPINE1 and SERPINE2) in EVT-conditioned media and/or cell lysates. Interleukin 11 (100 ng/ml) also did not regulate EVT cell adhesion or integrin expression. These data demonstrate that IL11 inhibits human EVT invasion via STAT3, indicating a likely role for IL11 in the decidual restraint of EVT invasion during normal pregnancy.
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PMID:Interleukin 11 inhibits human trophoblast invasion indicating a likely role in the decidual restraint of trophoblast invasion during placentation. 1898 31

In chronic arthritis cartilage and bone destruction occur as a consequence of synovial inflammation. It is mainly mediated by matrix metalloproteinases and RANKL-OPG pathways. Data on synovial fluid levels of these mediators in enthesitis related arthritis subtype (ERA) of JIA are not available. MMP-1, MMP-3, TIMP, sRANKL and OPG levels were measured in synovial fluid from patients with ERA and compared with other arthritides, polyarticular (Poly) JIA, RA and osteoarthritis (OA). sRANKL was detectable in 25/41 of ERA patients, 4/16 of Poly JIA patients. Median SF sRANKL level in patients with ERA was higher as compared to OA (p < 0.001) and poly JIA (p < 0.05) but were comparable to RA. The median OPG level in ERA was lower as compared to OA (p < 0.001), comparable to RA but was higher than poly JIA (p < 0.001). sRANKL/OPG ratio was significantly higher in ERA and Poly JIA compared to OA (p < 0.0001, p < 0.0001 respectively). The median MMP3 levels in ERA (74 microg/ml) was lower as compared to poly JIA (410 microg/ml; p < 0.0001) and RA (340 ug/ml; p < 0.0001) but was comparable to OA (107 microg/ml). The median level of ProMMP1 in ERA (0.70 microg/ml) was lower as compared to RA (2.9 microg/ml; p < 0.0001) and poly JIA but was elevated as compared to OA patients (0.1 microg/ml; p < 0.0001). TIMP1 levels in ERA were higher than poly JIA and RA patients. MMP3/TIMP1 ratio was lower in ERA compared to polyarticular JIA patients (p < 0.05). Ours is the first study reporting elevated sRANKL and reduced OPG levels and elevated sRANKL/OPG ratio in SF of children with JIA resulting in a mileu associated with bone loss. In addition, ERA patients had lower MMP level as well as MMP/TIMP ratio as compared to poly JIA which may partly explain lesser degree of joint damage seen in ERA as compared to poly JIA.
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PMID:Synovial fluid RANKL and matrix metalloproteinase levels in enthesitis related arthritis subtype of juvenile idiopathic arthritis. 1905 52

Although anoikis resistance has been considered a hallmark of malignant phenotype, the causal relation between neoplastic transformation and anchorage-independent growth remains undefined. We developed an experimental model of murine melanocyte malignant transformation, where a melanocyte lineage (melan-a) was submitted to sequential cycles of anchorage blockade, resulting in progressive morphologic alterations, and malignant transformation. Throughout this process, cells corresponding to premalignant melanocytes and melanoma cell lines were established and show progressive anoikis resistance and increased expression of Timp1. In melan-a melanocytes, Timp1 expression is suppressed by DNA methylation as indicated by its reexpression after 5-aza-2'-deoxycytidine treatment. Methylation-sensitive single-nucleotide primer extension analysis showed increased demethylation in Timp1 in parallel with its expression along malignant transformation. Interestingly, TIMP1 expression has already been related with negative prognosis in some human cancers. Although described as a MMP inhibitor, this protein has been associated with apoptosis resistance in different cell types. Melan-a cells overexpressing Timp1 showed increased survival in suspension but were unable to form tumors in vivo, whereas Timp1-overexpressing melanoma cells showed reduced latency time for tumor appearance and increased metastatic potential. Here, we demonstrated for the first time an increment in Timp1 expression since the early phases of melanocyte malignant transformation, associated to a progressive gene demethylation, which confers anoikis resistance. In this way, Timp1 might be considered as a valued marker for melanocyte malignant transformation.
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PMID:Tissue inhibitor of metalloproteinase 1 expression associated with gene demethylation confers anoikis resistance in early phases of melanocyte malignant transformation. 1995 95

In this study we propose a novel electrospinning fabrication process for the production of a nanofibrous matrix composed of collagen and hyaluronate. This procedure utilized 1,1,1,3,3,3-hexafluoro-2-propanol and formic acid as a mixed solvent. Fluorescence microscopy photographs revealed that the resulting electrospun nanofibers contained both collagen and hyaluronate. The mean diameter of the composite nanofibrous matrix (as observed using scanning electron micrographs) was approximately 200nm; this dimension is similar to that of native fibrous protein within the extracellular matrix. The expression of proteinases (e.g. matrix metalloproteinases, MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in epidermal repair during wound healing. Moreover, the characteristics of scarless wounds are known to be related to a decreased ratio of TIMP to MMP expression. In the present study the ratio of expression of TIMP1 to MMP1 was lower in foreskin fibroblast cells that were cultured on a hyaluronate-collagen composite nanofibrous matrix than in those cultured on an exclusively collagen nanofibrous matrix. This indicates that the hyaluronate-collagen composite nanofibrous matrix could potentially be used as a wound dressing for the regeneration of scarless skin.
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PMID:Electrospun hyaluronate-collagen nanofibrous matrix and the effects of varying the concentration of hyaluronate on the characteristics of foreskin fibroblast cells. 2003 7

PURPOSE. The migration and invasion of tumor cells correlate with the interaction between MMP and TIMP. Therefore, the purpose of this study was to determine the role of MMP-9, MMP-10, and TIMPs in pterygium formation and progression. METHODS. MMP-9, MMP-10, and TIMP proteins were studied using immunohistochemistry on 82 pterygial specimens and 30 normal conjunctivas. Pterygium epithelial cells (PECs), cultured in a serum-free culture medium, and siRNA were used to knock down TIMP gene expression to understand the role of TIMP in pterygium invasion. RESULTS. Among the 82 pterygial samples, 29 specimens (35.4%) were positive for MMP-9 expression, 28 were positive for MMP-10 (34.1%), and 59 were positive for TIMP1 (72.0%). Staining for MMPs was limited to the cytoplasm of the epithelial layer. The TIMP staining was detected in the pterygium epithelium, fibroblasts and corneal epithelium. In the cell model, cell invasion and migration ability increased in TIMP knockdown PECs compared with the parental control. CONCLUSIONS. MMP-9 and MMP-10 may each play a role in pterygium formation, and TIMPs may contribute to pterygium invasion inhibition.
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PMID:Effect of TIMP-1 and MMP in pterygium invasion. 2020 65

The matrix metalloproteinases (MMPs) constitute a large family of zincand calcium-dependent endopeptidases that cleave extracellular matrix components (1). Hence, MMPs are classified according to their substrate specificities: interstitial collagenases, stromelysins, gelatinases, membrane-type matrix metalloproteinases (MT-MMPs), and elastase (Table 1). The regulation of MMP activity involves gene expression, proteolytic processing of the propeptides to active forms, and inhibition by specific tissue inhibitors of matrix metalloproteinase (TIMPs). MMPs are involved in situations that require extracellular matrix remodeling, including wound healing, development, inflammation, fibrosis angiogenesis, and tumor invasion (2-5). Several complementary methods have provided an insightful description of the expression levels of MMPs and their pathological correlates. These include immunohistochemistry and Northern, Western, and dot blots. Additionally, the activity of MMPs is evaluated by gel substrate analysis. This approach has demonstrated that an increase in the expression of MMP2 (6,7), MT1-MMP (7), TIMP1, and TIMP2 (8-10) is associated with liver fibrosis. Similarly, in hepatocellular carcinomas, a high expression of MMP2, MMP9, MT1-MMP, and matrilysin is related to tumor aggressiveness (11-14). Consistently, by gel substrate analysis, MMP2 activity is increased in primary and secondary liver cancers (13,15,16). By in situ hybridization, the sources of.
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PMID:Assessing matrix metalloproteinase expression and activity in hepatocellular carcinomas. 2134 Oct 53

In this study, we identified differential expression of immunoreactive matrix metalloproteinase 2 (MMP2)/gelatinase A, membrane-anchored MT1-MMP/MMP14, and human relaxin-2 (RLN2) in human benign and malignant thyroid tissues. MMP2 and MT1-MMP were detected in the majority of thyroid cancer tissues and colocalized with RLN2-positive cells. MMP2 was mostly absent in goiter tissues and, similar to RLN2, may serve as a marker for thyroid cancer. MMP2 and MT1-MMP were identified as novel RLN2 targets. RLN2 caused a significant downregulation of tissue inhibitor of MMP (TIMP) 3 protein levels but did not change the expression levels of MMP13, and TIMP1, TIMP2, and TIMP4 in human thyroid carcinoma cells. RLN2 failed to affect the expression of MMP1, 3, 8, and 9 in the thyroid carcinoma cells investigated. Stable RLN2 transfectants secreted enhanced levels of bioactive MMP2 which contributed to the increased collagenolytic activity and in vitro invasiveness into collagen matrix by human thyroid cancer cells. Three-dimensional reconstitution of confocal fluorescent microscopy images revealed larger-sized invadopodia, with intense MT1-MMP accumulation at the leading migrating edge in RLN2 transfectants when compared with enhanced green fluorescent protein clones. In RLN2 transfectants actin stress fibers contributed to pseudopodia formation. In conclusion, enhanced tumor cell invasion by RLN2 involves the formation of MT1-MMP-enriched invadopodia that lead to increased collagenolytic cell invasion by human thyroid cancer cells.
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PMID:Relaxin enhances the collagenolytic activity and in vitro invasiveness by upregulating matrix metalloproteinases in human thyroid carcinoma cells. 2149 87

Tissue inhibitors of metalloproteinases (TIMPs) play an important role in extracellular matrix homeostasis by regulating MMP activity. Although they were initially considered inhibitors of tumor growth and metastasis, recently their role in cancer progression has been controversial. The aim of our study was to compare the immunohistochemical expression of TIMP1 and TIMP2 between an uncontrollably invasive phenomenon (cancer) and an "in situ" process (trophoblast invasion) in an effort to assess any differential role of these molecules between these two distinct phenomena and therefore to understand better their contribution in cancer invasion and migration. We performed an immunohistochemical analysis of 50 carcinomas (colorectal, gastric, breast, pulmonary, and renal) and 40 first trimester gestations. The marker expression was evaluated semiquantitatively, separately in cancer parenchymal and trophoblastic cells as well as in malignant stromal and decidual cells, according to a percentage scale (0, <10, 10-50, and >50%) and according to staining intensity (0, +, ++, and +++). Our results showed that there was no statistically significant difference in TIMP1 expression between cancer parenchymal cells and trophoblastic cells. On the other hand, TIMP1 was expressed more often in decidual cells than in cancer stromal cells. Immunostaining for TIMP2 was more extensive and intense both in trophoblastic and decidual cells than in cancer parenchymal and stromal cells, respectively. The reduced expression of TIMP2 in metastatic carcinomas by comparison with non-metastatic gestation specimens underlines its importance in cancer invasion and migration. On the other hand, TIMP1 was more expressed in decidua than cancer stroma, but at the same time showed no statistically significant difference between cancer parenchyma and trophoblasts, highlighting its multifunctional activity in cancer progression.
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PMID:Comparative study of the immunohistochemical expression of tissue inhibitors of metalloproteinases 1 and 2 between clearly invasive carcinomas and "in situ" trophoblast invasion. 2178 79


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