Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amphoterin is 1 ligand of the receptor for advanced glycation end products (RAGE). We studied expression of amphoterin and RAGE mRNA and proteins in colorectal carcinoma cells and investigated their associations with the invasive activities of cells exposed to advanced glycation end products (AGE). Expression of RAGE and amphoterin was examined in 4 colorectal carcinoma cell lines. All cell lines expressed both RAGE and amphoterin. The effects of RAGE and amphoterin on cell growth (MTT assay), migration (wound healing assay) and invasion (in vitro invasion assay) were tested by treatment of cells with RAGE and amphoterin antisense S-oligodeoxynucleotides (ODNs). Cell growth, migration and invasion were inhibited significantly in Colo320 and WiDr carcinoma cells treated with RAGE and amphoterin antisense S-ODNs compared with sense-treated cells. Differences in ligand activity between amphoterin and AGE were examined with AGE-bovine serum albumin (BSA). AGE-BSA decreased cell growth, migration and invasion of amphoterin antisense S-ODN-treated Colo320 and WiDr cells compared with those of cells treated with Colo320 conditioned medium. Phosphorylation of extracellular signal-regulated kinase-1/2, Rac1 and AKT and production of matrix metalloproteinase 9 were increased to a greater degree by amphoterin than by AGE-BSA. In contrast, production of inducible nitric oxide synthase and nuclear factor-kappaBp65 were increased to a greater degree by AGE-BSA than by amphoterin.
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PMID:Differential effects between amphoterin and advanced glycation end products on colon cancer cells. 1264 Jun 79

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was originally considered to have activity against malignant disease. However, recent studies suggest TNF-alpha may also act as an endogenous tumor promoter. In the present work, mice deficient in TNF-alpha either genetically (TNF-alpha(-/-)) or after blockade with a neutralizing antibody (cV1q) were used to investigate the role of TNF-alpha in skin tumor development. Papillomas were induced in wild-type (wt) mice after treatment of skin with the initiating agent 9,10-dimethyl-1,2-benzanthracene followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 15 weeks. TNF-alpha(-/-) mice were resistant to papilloma development when compared with wt mice on C57Bl/6J, 129/SvEv, and BALB/c genetic backgrounds. Primary murine keratinocytes (newborn keratinocytes) and skin homogenates were used to characterize TPA-stimulated TNF-alpha expression. TPA induced TNF-alpha protein in newborn keratinocytes in vitro and epidermis in vivo. Neutralization of TNF-alpha protein with cV1q in vivo for 0-15 weeks of promotion significantly decreased skin tumor development after 9,10-dimethyl-1,2-benzanthracene/TPA treatment. cV1q treatment during the early stages of tumor promotion (0-6 weeks) was equally effective. These data suggest that early induction of TNF-alpha is critical for skin tumor promotion. cV1q also reduced TPA-stimulated expression of matrix metalloproteinase 9 and granulocyte macrophage colony-stimulating factor, proteins that are differentially regulated in wt and TNF-alpha(-/-) epidermis. Treatment of the 410.4 transplantable breast carcinoma with cV1q reduced tumor growth in vivo, illustrating that inhibition of tumor growth through neutralization of TNF-alpha is not limited to skin carcinogenesis. These results provide further evidence for procancer actions of TNF-alpha and give some rationale for use of TNF-alpha antagonists in cancer prevention and treatment.
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PMID:An anti-tumor necrosis factor-alpha antibody inhibits the development of experimental skin tumors. 1274 6

We reconstituted a three-dimensional gastric carcinoma model similar to invasive gastric carcinoma tissue. This model consists of a human gastric carcinoma cell line, GCTM-1, a human fibroblast cell line, TIG-1-20, and transforming growth factor-beta (TGF-beta)-containing type I collagen gel. Using this model, we were able to observe the growth of the two cell types, especially carcinoma cell invasive growth, in real time for more than 30 days. TGF-beta and TIG-1-20 were essential for GCTM-1 invasive growth and proliferation, respectively. TGF-beta induced the enhanced expression of matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA) in GCTM-1 at both the protein and enzymatic activity levels. The TGF-beta-induced invasion of GCTM-1 was inhibited by MMP9- or uPA-antisense (AS) oligonucleotide transfection to GCTM-1. When exogenous interferon-gamma (IFN-gamma) was added to this model, TGF-beta-dependent GCTM-1 invasion was significantly inhibited, concomitant with the decreased expression of MMP9 and uPA. The intracellular signal transduction of Smad was examined to analyse the mechanism of the inhibitory effect of IFN-gamma. TGF-beta accelerated the phosphorylation of Smad2/3 and nuclear translocation of the Smad2/3-Smad4 complex in GCTM-1, but these TGF-beta-induced effects were significantly inhibited by IFN-gamma-induced Smad7 expression. When GCTM-1 was cotransfected with AS oligonucleotide of Smad2 and Smad3, the TGF-beta-induced invasion of GCTM-1 disappeared. In addition, the inhibitory effect of IFN-gamma on TGF-beta-dependent GCTM-1 invasion vanished by the AS oligonucleotide of Smad7 transfection. These results indicate that IFN-gamma inhibits TGF-beta-dependent GCTM-1 invasion through cross-talk in the Smad pathway. IFN-gamma may be a new therapeutic tool for TGF-beta-expressed invasive carcinomas.
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PMID:Interferon-gamma suppresses transforming growth factor-beta-induced invasion of gastric carcinoma cells through cross-talk of Smad pathway in a three-dimensional culture model. 1458 10

Local disruption of the integrity of both the myoepithelial cell layer and the basement membrane is an indispensable prerequisite for the initiation of invasion and the conversion of human breast ductal carcinoma in situ (DCIS) to infiltrating ductal carcinoma (IDC). We previously reported that human endometase/matrilysin-2/matrix metalloproteinase (MMP) 26-mediated pro-gelatinase B (MMP-9) activation promoted invasion of human prostate carcinoma cells by dissolving basement membrane proteins (Y. G. Zhao et al., J. Biol. Chem., 278: 15056-15064, 2003). Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K(i) values of 1.6 and 0.62 nM, respectively. TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro. The expression levels of MMP-26, MMP-9, TIMP-2, and TIMP-4 proteins in DCIS were significantly higher than those in IDC, atypical intraductal hyperplasia, and normal breast epithelia adjacent to DCIS and IDC by immunohistochemistry and integrated morphometry analysis. Double immunofluorescence labeling and confocal laser scanning microscopy revealed that MMP-26 was colocalized with MMP-9, TIMP-2, and TIMP-4 in DCIS cells. Higher levels of MMP-26 mRNA were also detected in DCIS cells by in situ hybridization.
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PMID:Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion. 1474 73

The ability of cancer cells to proliferate abnormally and invade surrounding tissue is among the most important features of the malignant phenotype. The mechanisms by which the mitogen activated protein kinase (MAPK) cascade regulates these phenotypes have been investigated for many years. Activated GTP bound Ras binds the upstream protein kinases Raf-1 and B-Raf. The MAPK kinases 1 and 2, known as MKK or MEK, are phosphorylated and activated by Raf. MEKs phosphorylate the extracellular signal regulated kinases ERK1 and ERK2. A unique member of the MAPK family is p97MAPK, the human homolog of rat ERK3. p97MAPK is ubiquitously expressed but whether its cellular functions are different from ERK1 and ERK2 is unknown. p97MAPK is highly expressed in human cancer cell lines. In the present study, expression of p97MAPK was unique among the ERK family in that its expression was induced when human carcinoma cell lines are plated on type IV collagen. This increased expression correlated with slower cancer cell proliferation on collagen compared to plastic tissue culture dishes. Overexpression of p97MAPK was sufficient to inhibit cellular proliferation with concomitant changes in cell cycle regulatory protein expression. p97MAPK also inhibited cancer cell migration and invasion by decreasing Rac1 expression but not that of matrix metalloproteinase 9 which is regulated by other ERKs. These data represent the first reported function of p97MAPK in human cancer cells.
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PMID:Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines. 1506 37

Intratumor (i.t.) injection of 35 mg/kg/day NAMI-A for six consecutive days to CBA mice bearing i.m. implants of MCa mammary carcinoma reduces primary tumor growth and particularly lung metastasis formation, causing 60% of animals to be free of macroscopically detectable metastases. The i.t. treatment allows study of the effects of NAMI-A on in vivo tumor cells exposed to millimolar concentrations for a relatively prolonged time. Under these conditions, NAMI-A reduces the number of CD44+ tumor cells and changes tumor cell phenotype to a lower aggressive behavior, as shown by scanning electron microscopy analysis. On primary tumor site, NAMI-A causes unbalance between 2n and aneuploid cells in favor of lymphocytes. Furthermore, in tumor tissue, nitric oxide production is increased and active matrix metalloproteinase 9 is decreased, and these effects are accompanied by a reduced hemoglobin concentration. These data are in agreement with the reduction of tumor invasion and metastasis and suggest the therapeutic usefulness of NAMI-A in neoadjuvant or tumor reduction treatments for preventing metastasis formation. These data further stress the usefulness of intratumor treatments as experimental preclinical model for studying in vivo the mechanism of tumor cell interactions after prolonged exposure to ruthenium-based compounds to be developed for metastasis inhibition.
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PMID:Intratumoral NAMI-A treatment triggers metastasis reduction, which correlates to CD44 regulation and tumor infiltrating lymphocyte recruitment. 1507 81

We have shown recently that the hyaluronan receptor, CD44, and matrix metalloproteinase 9 (MMP-9) form a complex on the surface of TA/St mouse mammary carcinoma cells that activates latent transforming growth factor-beta (TGF-beta) and is required for tumor invasion. Disruption of the CD44/MMP-9 complex by expression of soluble CD44 results in the loss of tumor invasiveness and abrogates tumor cell survival in host lung parenchyma following intravenous injection into syngeneic mice. To explore the molecular nature of the survival signals derived from the CD44/MMP-9 complex during the development of tumor metastasis, we investigated the possibility that activation of latent TGF-beta by the CD44/MMP-9 complex is responsible for tumor cell survival in host lung parenchyma. TA3 cells overexpressing dominant negative soluble CD44 (TA3sCD44), which compromises native CD44 function and the ability of TA3 cells to develop metastases, were transfected with constitutively active or latent TGF-beta2 and tested for their ability to form tumors in syngeneic mice. Our results demonstrate that expression of the constitutively active, but not the latent, form of TGF-beta2 rescues TA3sCD44 cells from apoptosis during lung colonization. These observations provide evidence that activation of latent TGF-beta constitutes an event downstream of CD44-dependent signals that is required for tumor cell survival and metastatic colony formation. The functional axis composed of CD44, MMP-9 and TGF-beta may therefore play an important role in the metastatic proclivity of selected tumor types.
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PMID:Transforming growth factor-beta facilitates breast carcinoma metastasis by promoting tumor cell survival. 1538 73

EBV latent membrane protein 1 (LMP1) is an oncoprotein frequently expressed in nasopharyngeal carcinoma. We have generated transgenic mice expressing the nasopharyngeal carcinoma-derived CAO strain of LMP1 and LMP1 of the B95-8 strain, using the viral ED-L2 promoter for epithelial expression. LMP1(CAO) and LMP1(B95-8) induce transforming growth factor alpha expression and epidermal hyperplasia. However, levels of total epidermal growth factor receptor (EGFR) decline with the appearance of phosphorylated EGFR products, suggesting that the negative feedback loop upon EGFR expression is intact or that there is faster turnover at these early stages of carcinogenesis. In the L2LMP1(CAO) mice, increased levels of vascular endothelial growth factor are also seen at an early stage in the skin. As the phenotype worsens, with increasing hyperplasia and vascularization leading to keratoacanthoma, p16(INK4a) and matrix metalloproteinase 9 expression is induced. The lesions can progress spontaneously to carcinoma. Carcinoma cell lines developed from these mice show high levels of total and phosphorylated EGFR. These data show that the induction of signaling through EGFR by LMP1 is an early event in carcinogenesis and that any inhibition upon EGFR expression is lifted during progression. Furthermore, expression of LMP1 is not sufficient to inhibit induction of p16(INK4a) in response to abnormal proliferation. These data are consistent with the cooperative effects seen between LMP1 and loss of the INK4a locus in transgenic mice and with the frequency of loss of this locus in EBV-associated nasopharyngeal carcinoma.
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PMID:Epstein-Barr virus latent membrane protein 1 (CAO) up-regulates VEGF and TGF alpha concomitant with hyperlasia, with subsequent up-regulation of p16 and MMP9. 1620 53

Although it has been shown that the cross-talk between osteoblasts and tumor cells stimulates proliferation and invasion of prostate carcinoma (PCa) cells, the molecular mechanisms underlying this event are largely unknown. In this study, we demonstrated that the PCa cells, PC3, derived from bone metastasis, undergo changes of their invasive capability if grown in the presence of osteoblast-derived conditioned media (OBCM). Specifically, they were able to organize tridimensional structures in Matrigel, such as large branching colonies, tube-like structures and clusters of proliferating cells, after treatment. At the ultrastructural level, we observed that PC3 cells grown in the presence of OBCM presented an increment of membrane activity with a blast of shed membrane vesicles from the cell surface. After 6 h of incubation, protein content was approximately 5-fold more elevated in vesicles isolated from PC3 cells cultured in OBCM than in unstimulated cultures. Gelatin zymography of vesicles collected from OBCM-treated PC3 cells showed an increment of lytic bands of MMP family members identified as pro-enzymatic and active forms of gelatinase A (MMP-2) and gelatinase B (MMP-9). By casein-plasminogen zymography, this latter culture also presented an elevated level of high-molecular weight urokinase plasminogen activator (HMW-uPA). Purified vesicles from OBCM-treated PC3 cells incubated with Matrigel cleaved its components more efficiently than vesicles from untreated PC3 cells. Collectively, these findings indicate that osteoblasts produce factor/s able to modify the invasive capability of prostate cancer cells, increasing the amount of shed vesicles and of their associated lytic enzymes.
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PMID:Osteoblast-conditioned media stimulate membrane vesicle shedding in prostate cancer cells. 1652 40

The matrix metalloproteinases (MMPs) are a family of proteolytic zinc-containing enzymes, which are responsible for the breakdown of the extracellular matrix components in pathological and physiological conditions. They are involved in basement membrane disruption, stroma and blood vessel penetration, metastasis and more recently there is evidence that they participate in tumor growth and angiogenic events. Matrix metalloproteinase 2 and 9 (MMP 2 and 9) belong to the gelatinases, a subgroup of MMPs, and have the capacity to degrade the triple helix type IV collagen of basal lamina of the basement membrane. With the present study, we tried to demonstrate the expression of MMP-9 immunohistochemically, comparatively in benign, premalignant and malignant lesions of the larynx. We studied 154 laryngeal lesions including 55 squamous cell carcinomas, 8 in situ carcinomas, 54 cases of dysplasia (of low and intermediate grade), 13 papillomas and 24 cases of keratosis. Overexpression of MMP 9 was observed in 74.4% and 50% in invasive and in situ squamous cell carcinomas respectively. In dysplastic cases, in papillomas and in keratoses the percentage of overexpression was 62.9%, 61.53% and 54.16% respectively and the expression of MMP-9 was significantly higher in invasive squamous cell carcinomas compared to dysplasias (p=0.000004). Also significantly higher was the expression of MMP-9 in dysplastic cases compared to papillomas (p=0.023). The MMP-9 expression was related neither to survival nor to the other available clinicopathological parameters (tumor size, grade, clinical stage, lymph node status and patient age). In conclusion, our study indicates that the expression of MMP-9 is up-regulated in a stepwise fashion, with two main steps, the first one, when a dysplastic lesion evolves and the next one, when the dysplasia progresses to invasive carcinoma.
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PMID:Expression of matrix metalloproteinase-9 (gelatinase B) in benign, premalignant and malignant laryngeal lesions. 1652 70


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