Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.23 (MMP)
4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acquisition of a migratory/invasive phenotype by tumor cells is characterized by the loss of cell-cell adhesion contacts and the expression of degradative properties. In this study, we examined the effect of the disorganization of occludin/zonula occludens (ZO)-1 tight junction (TJ) complexes on the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP). We first compared the expression of MT1-MMP and the localization of occludin/ZO-1 complexes in breast tumor cell lines displaying various degrees of invasiveness. We showed that the expression of MT1-MMP in invasive breast tumor cell lines correlates with the absence of occludin and with a cytoplasmic localization of ZO-1. In contrast, noninvasive cell lines displayed a membrane staining for both ZO-1 and occludin and did not express MT1-MMP. In vivo, cytoplasmic ZO-1 and MT1-MMP could be detected in invasive tumor clusters of human breast carcinomas. We then used RNA interference strategy to inhibit ZO-1 expression in invasive BT549 cells and to evaluate the effect of ZO-1 down-regulation on MT1-MMP expression. We observed that ZO-1 small interfering RNA transfection down-regulates MT1-MMP mRNAs and proteins and subsequently decreases the ability of tumor cells to invade a reconstituted basement membrane in a Boyden chamber assay. Inversely, transfection of expression vectors encoding wild-type ZO-1 or the NH2-terminal fragment of ZO-1 comprising the PSD95/DLG/ZO-1 domains in BT549 activated a human MT1-MMP promoter luciferase reporter construct and increased cell invasiveness. Such transfections concomitantly activated the beta-catenin/TCF/LEF pathway. Our results therefore show that ZO-1, besides its structural role in TJ assembly, can intervene in signaling events promoting tumor cell invasion.
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PMID:Membrane-type 1 matrix metalloproteinase expression is regulated by zonula occludens-1 in human breast cancer cells. 1614 Sep 36

Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
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PMID:Molecular prognostic markers in pancreatic cancer: a systematic review. 1614 90

Matrilysin, MMP-7, is an important target for anti-metastasis therapy of colorectal cancer because it is a strong proteolytic factor secreted from the cancer cell itself and it induces tumor angiogenesis. In a previous report, we showed that matrilysin accelerated human umbilical vein endothelial cell (HUVEC) proliferation in low serum conditioned medium. In the present study, we show that matrilysin stimulation decreased VE-cadherin expression, induced accumulation of beta-catenin in the nucleus of the HUVEC, and up-regulated matrilysin mRNA expression. These results compel a hypothesis that matrilysin cleaves VE-cadherin and releases beta-catenin from the VE-cadherin/catenin complex; the free beta-catenin can activate T-cell factor (Tcf) DNA binding protein, which accelerates cell proliferation and matrilysin expression.
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PMID:Matrilysin (MMP-7) degrades VE-cadherin and accelerates accumulation of beta-catenin in the nucleus of human umbilical vein endothelial cells. 1639 47

The oncogenic beta-catenin/T-cell factor (TCF) signal is a common trigger inducing expressions of various cancer-related genes and is activated in various types of human malignancy. The aim of this study was to create an effective double-stranded DNA decoy that would interfere with endogenous TCF hyperactivity in tumor cells. We first established the TCF-activated model using nontumor human embryonic kidney 293 (HEK293) cells by introducing a beta-catenin cDNA. Based on a consensus TCF-binding sequence in the cyclin D1 and c-myc promoters, several double-stranded oligodeoxynucleotides were designed and tested for their ability to inhibit TCF activity in the HEK293 model. Among them, the 18-mer oligodeoxynucleotide stably formed double-stranded DNA and efficiently inhibited TCF activity. FITC-labeled oligodeoxynucleotide was efficiently incorporated into the nucleus at 6 hours and remained within cells for up to 72 to 96 hours. When compared with scrambled oligodeoxynucleotide, we found that the 18-mer TCF decoy significantly inhibited TCF activity and promoter activities of the downstream target genes, such as cyclin D1, c-myc, and matrix metalloproteinase 7 in HCT116 colon cancer cells. Reverse transcription-PCR assays indicated that mRNA expression of these genes decreased with treatment of the TCF decoy. Proliferation assay showed that the TCF decoy significantly inhibited growth of HCT116 tumor cells, but not of nontumor HEK293 cells. Our data provide evidence that the TCF decoy reduced both TCF activity and transcriptional activation of downstream target genes. Thus, this TCF decoy is potentially an efficient and nontoxic molecular targeting therapy for controlling malignant properties of cancer cells.
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PMID:Construction of a novel DNA decoy that inhibits the oncogenic beta-catenin/T-cell factor pathway. 1664 70

E-cadherin/beta-catenin complex has a critical role in cell-cell adhesion. beta-Catenin is a critical component of the highly conserved Wnt signaling pathway that regulates cell proliferation and differentiation. Wnt signaling leads to the stabilization of cytosolic beta-catenin and to translocation to the nucleus, where it binds with T-cell factor and promotes the transcription and changes in target gene expression, including matrix metalloproteinases. In this study, we analyzed paraffin-embedded specimens from 42 patients with pT3 rectosigmoid cancer for E-cadherin, beta-catenin, and matrix metalloproteinase-7(MMP-7, matrilysin) expression using immunohistochemistry. Seventy-four and 79% of tumors expressed beta-catenin and E-cadherin, respectively. Nuclear expression of beta-catenin was detected only in 26.1% of tumors. Forty-five percent of the rectosigmoid cancers showed strong expression of MMP-7. It was revealed that membranous or cytoplasmic beta-catenin expression was significantly related to E-cadherin and MMP-7 expression. No significant association was seen between E-cadherin, beta-catenin, or MMP-7 expression and some clinicopathologic features. Our results may contribute to the functional interaction between beta-catenin and MMP-7. Further studies on Wnt/beta-catenin and MMP-7 gene activity and protein expression are necessary to better understand the pathogenesis of colorectal carcinoma.
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PMID:E-cadherin, beta-catenin adhesion complex and relation to matrilysin expression in pT3 rectosigmoid cancers. 1867 69

Desmoid tumors (desmoid-type fibromatoses) are locally aggressive soft tissue tumors associated with the Wnt/beta-catenin signaling pathway (APC-beta-catenin-Tcf pathway). Matrix metalloproteinase-7, which is one of the target genes of the Wnt/beta-catenin signaling pathway, has been reported to play an important role in tumor progression. We examined the immunohistochemical expression of beta-catenin and matrix metalloproteinase-7 in 72 samples (63 primary and 9 recurrent samples, 63 patients) of sporadic desmoid tumors without familial adenomatous polyposis, and the genetic alteration of the beta-catenin gene in 33 frozen materials (22 primary and 11 recurrent samples, 22 patients). We further examined messenger RNA expression of matrix metalloproteinase 7 by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and compared the results with those of normal skeletal muscles. Immunohistochemically, there was a statistically significant correlation between widespread nuclear expression of beta-catenin and overexpression of matrix metalloproteinase-7 (P < .01 in extra-abdominal desmoid, Fisher test). There were 7 missense point mutations in the 22 primary frozen samples (32%). In the beta-catenin mutated group, matrix metalloproteinase-7 messenger RNA expression was significantly higher than that of the beta-catenin wild-type group (P = .0018, Mann-Whitney U test). Our results suggest that the matrix metalloproteinase-7 gene may be up-regulated by mutated or continuously elevated beta-catenin protein and that the matrix metalloproteinase-7 gene may also be targeted in the Wnt/beta-catenin signaling pathway in sporadic desmoid tumors.
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PMID:Correlation between beta-catenin widespread nuclear expression and matrix metalloproteinase-7 overexpression in sporadic desmoid tumors. 1871 18

Overexpression of cyclooxygenase 2 (COX2) and uncontrolled wingless and Int (Wnt)-signaling pathway have long been suggested to play crucial roles in colorectal cancer. Studies show that selective COX2 inhibitors possess great potential as chemopreventive agents for colon cancer. Recent studies suggest that targeting COX2 and epidermal growth factor receptor (EGFR) may provide better therapeutic strategy than inhibiting either single target and that this may alleviate the problem of COX2 inhibitor-associated side effects. Therefore, there have been intensive efforts to develop novel dietary substances that target COX2 and EGFR activation. Fisetin is a naturally occurring flavonoid commonly found in various vegetables and fruits. We found that the treatment of COX2-overexpressing HT29 human colon cancer cells with fisetin (30-120 microM) resulted in induction of apoptosis, downregulation of COX2 protein expression without affecting COX1 and inhibited the secretion of prostaglandin E2. Treatment of cells with fisetin also inhibited Wnt-signaling activity through downregulation of beta-catenin and T cell factor 4 and decreased the expression of target genes such as cyclin D1 and matrix metalloproteinase 7. Fisetin treatment of cells also inhibited the activation of EGFR and nuclear factor-kappa B (NF-kappaB). Finally, the formation of colonies in soft agar was suppressed by fisetin treatment. Taken together, we provide evidence that the plant flavonoid fisetin can induce apoptosis and suppress the growth of colon cancer cells by inhibition of COX2- and Wnt/EGFR/NF-kappaB-signaling pathways. We suggest that fisetin could be a useful agent for prevention and treatment of colon cancer.
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PMID:A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. 1903 88

Expression of oncogenic K-Ras is frequently observed in non-small-cell lung cancer. However, oncogenic K-Ras is not sufficient to transform lung epithelial cells and requires collaborating signals that have not been defined. To examine the biological effects of K-Ras in nontransformed lung epithelial cells, stable transfectants were generated in RL-65 cells, a spontaneously immortalized lung epithelial cell line. Expression of K-Ras resulted in extracellular signal-regulated kinase (ERK) activation, which mediated induction of cyclooxygenase (COX)-2 and increased prostaglandin E(2) production. Epithelial cells expressing oncogenic K-Ras showed increased proliferation in two- and three-dimensional tissue culture and delayed formation of hollow acinar structures in three-dimensional matrigel cultures. These affects were mediated through COX-2-dependent activation of beta-catenin signaling and inhibition of apoptosis. ERK activation also led to induction of metalloproteinase (MMP)-9 and cleavage of E-cadherin at two specific sites. This resulted in partial disruption of adherens junctions as determined by decreased transepithelial resistance (TER), and disruption of E-cadherin/beta-catenin interactions. An MMP-9 inhibitor reversed the decrease in TER and inhibited beta-catenin signaling. These data indicate that although expression of oncogenic K-Ras does not transform lung epithelial cells, it alters the phenotype of the cells by increasing proliferation and decreasing cell-cell contacts characteristic of epithelial cells.
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PMID:Oncogenic K-Ras regulates proliferation and cell junctions in lung epithelial cells through induction of cyclooxygenase-2 and activation of metalloproteinase-9. 1903 3

Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.
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PMID:Renal allografts with IF/TA display distinct expression profiles of metzincins and related genes. 1919 72

To confirm the usefulness of the radial flow type bioreactor (RFB) for a three-dimensional (3D) culture system, which provides a tissue architecture and molecular function mimicking the in vivo environment, molecular expression in the A431 human squamous carcinoma cell line during culture were analyzed under the physically different environments of 3D culture in the RFB, 2D culture in a monolayer as well as in nude mice. Time-dependent accumulation of autocrine transforming growth factor (TGF) beta1 was found in spent culture media obtained only from 3D cultured A431 cancer cells, which grew well with a stratified-sheet morphology. Cells in the RFB overexpressed matrix metalloproteinase 7 (MMP7) and showed an increased release of soluble 80-kDa fragments of E-cadherin into the media time-dependently, resulting in the reduction of E-cadherin protein at the cell surface without down-regulation of the mRNA. beta-Catenin and its nuclear partner, LEF1, were up-regulated and Wnt protein secretion was also accelerated. Additional up-regulation of the transcriptional factors, HMGA2 and down-stream Slug, was noted. TGFbeta1-dependent, MMP7-mediated up-regulation of beta-catenin/LEF1 signaling and TGFbeta1-activated HMGA2 pathways consequently converged with Slug overexpression, due to disassembly and further repression of E-cadherin expression, which was reproducible in the epithelial mesenchymal transition process without any manipulation. Other transcriptional factors, Notch/HEY1 and NF-kappaB, were also up-regulated in 3D-cultured cells. These signals recruited molecules related to extracellular matrix-cell remodeling and angiogenesis. Expression of several representative molecules in the 3D cultured cells was parallel with that in xenotransplanted A431 tumor tissues in nude mice. 3D culture of tumor cells in the RFB is a useful tool for cancer experimental biology and evaluation of cancer therapeutic-like systems in nude mice.
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PMID:Three-dimensional culture using a radial flow bioreactor induces matrix metalloprotease 7-mediated EMT-like process in tumor cells via TGFbeta1/Smad pathway. 1936 Mar 57


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