Synergy between plasminogen activator inhibitor-1 and Snail in tumoral migration
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE10395 | GEO | 2008/12/31
SECONDARY ACCESSION(S): PRJNA108147
REPOSITORIES: GEO
Similar Datasets
Project description:Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasivity. The Plasminogen Activation system (PAs), including urokinase (uPA), its receptor (uPAR), and its inhibitor (PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non proteolytic modulation of cell adhesion and migration. Thus, Snail and PAs both influence those processes and are over-expressed in cancers. In this study we aimed to determine first whether Snail activity is correlated with PAs components expression and second how this correlation can influence tumoral cell migration. Keywords: Tumoral migration Comparison the invasive breast cancer cell-line MDA-MB-231 expressing Snail (MDA-Neo) with its derived clone expressing a dominant negative form of Snail (Snail-DN). Expression of PAs mRNAs was performed by cDNA microarrays and real time quantitative RT-PCR. Wound healing assay was used to determine cell migration. PAI-1â??s distribution was assessed by immunostaining.
2010-06-24 | E-GEOD-10395 | biostudies-arrayexpress
Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease.
2011-05-03 | GSE29028 | GEO
Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.
2011-05-03 | E-GEOD-29028 | biostudies-arrayexpress
Project description:Analysis of uPA regulation of 4T1 tumor growth at gene expression level. The hypothesis tested in the present study was that overexpression of uPA in 4T1 tumor influence the tumor growth and metastasis related cell signaling pathway.
2012-05-31 | GSE38346 | GEO
Project description:Venkatraman2011 - PLS-UPA behaviour in the
presence of substrate competition
The posibility of ultrasensitivity and bistable activation of
PLS (Plasmin) and UPA (Urokinase-type plasminogen activator) in
the presence of substrate competition is explained here using a
mathematical model.
This model is described in the article:
Steady states and dynamics
of urokinase-mediated plasmin activation in silico and in
vitro.
Venkatraman L, Li H, Dewey CF Jr,
White JK, Bhowmick SS, Yu H, Tucker-Kellogg L.
Biophys. J. 2011 Oct; 101(8):
1825-1834
Abstract:
Plasmin (PLS) and urokinase-type plasminogen activator (UPA)
are ubiquitous proteases that regulate the extracellular
environment. Although they are secreted in inactive forms, they
can activate each other through proteolytic cleavage. This
mutual interplay creates the potential for complex dynamics,
which we investigated using mathematical modeling and in vitro
experiments. We constructed ordinary differential equations to
model the conversion of precursor plasminogen into active PLS,
and precursor urokinase (scUPA) into active urokinase (tcUPA).
Although neither PLS nor UPA exhibits allosteric cooperativity,
modeling showed that cooperativity occurred at the system level
because of substrate competition. Computational simulations and
bifurcation analysis predicted that the system would be
bistable over a range of parameters for cooperativity and
positive feedback. Cell-free experiments with recombinant
proteins tested key predictions of the model. PLS activation in
response to scUPA stimulus was found to be cooperative in
vitro. Finally, bistability was demonstrated in vitro by the
presence of two significantly different steady-state levels of
PLS activation for the same levels of stimulus. We conclude
that ultrasensitive, bistable activation of UPA-PLS is possible
in the presence of substrate competition. An ultrasensitive
threshold for activation of PLS and UPA would have
ramifications for normal and disease processes, including
angiogenesis, metastasis, wound healing, and fibrosis.
The cooperativity parameter "ci" was missing in the original
model. The parameter "ci" has been added to the added.
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BIOMD0000000630.
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2024-09-02 | BIOMD0000000630 | BioModels
Project description:Analysis of uPA regulation of 4T1 tumor growth at gene expression level. The hypothesis tested in the present study was that overexpression of uPA in 4T1 tumor influence the tumor growth and metastasis related cell signaling pathway. 4T1 cells were stably transduced by lentiviral vector expressing mouse uPA or empty vector. After day 7 of inoculation of 4T1 cells into fatpad of Balb/c mice. Total RNA was extracted from tumor samples (triplicate) using Qiagen total RNA isolation kit. The Illumina MouseWG-6 v2.0 Expression BeadChip (Illumina, Wallingford, CT) was used for gene expression. The raw data from the fluorescence intensity measurements of each array experiment was processed using GeneSpringGX v.11.0 software (Agilent, Santa Clara, CA). Statistical analysis, fold change calculations, and hierarchical clustering of the data were also performed in GeneSpring software. Genes that expressed significantly differently with more than 1.5-fold change and a p-value of <0.05 with respect to controls were taken into consideration. Gene expression data were further validated by qRT-PCR analysis. Pathway analysis was performed by MetaCore software (GeneGo, Inc, St. Joseph, MI).
2012-05-30 | E-GEOD-38346 | biostudies-arrayexpress
Project description:Mechanisms of urokinase plasminogen activator (uPA)-mediated atherosclerosis
| PRJNA140485 | ENA
Project description:In addition to immunodeficiency, host mice for chimeric mice with highly humanized liver should have hepatic malfunction in order to allow higher replacement rate of human hepatocytes in the liver. Urokinase-type plasminogen activator (uPA) whole gene transfer is often employed to achieve hepatic malfunction in the host mice. We have established uPA cDNA transfer that is far stable, as compared with traditional whole uPA gene transfer. Hepatic gene expression was quite similar between whole uPA gene transfer and uPA cDNA transfer after transplantation of the same lot of human hepatocyte (BD195),, as compared with the variation of gene expression after transplantation of different lots of human hepatocytes to host mice with whole uPA gene transfer.
2015-06-17 | GSE69936 | GEO
Project description:Synergy between plasminogen activator inhibitor-1 and Snail in tumoral migration
| PRJNA108147 | ENA
Project description:Inducible keratinocyte-specific ILEI overexpression in mice (K5-ILEIind) recapitulates many aspects of psoriasis following TPA challenge, primarily manifested by impaired epidermal differentiation and increased neutrophil recruitment. Mechanistically, ILEI triggers Erk and Akt signaling, which then activate STAT3 via Ser727 phosphorylation. Keratinocyte-specific ILEI deletion ameliorates TPA-induced skin inflammation. A transcriptomic ILEI signature obtained from the K5-ILEIind model shows enrichment in several signaling pathways also found in psoriasis and identifies urokinase as a targetable enzyme to counteract ILEI activity. Pharmacological inhibition of urokinase in TPA-induced K5-ILEIind mice results in significant improvement of psoriasiform symptoms by reducing ILEI secretion. The ILEI signature distinguishes psoriasis from healthy skin with uPA ranking among the top “separator” genes. Our study identifies ILEI as a key driver in psoriasis, indicates the relevance of ILEI-regulated genes for disease manifestation and shows the clinical impact of ILEI and urokinase as novel potential therapeutic targets in psoriasis.
2023-04-12 | E-MTAB-12849 | biostudies-arrayexpress