Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

Bock, Charles E. de; Wang, Yao

doi:10.1002/med.10054

Cited by 136 publications

(110 citation statements)

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“…In addition, most malignant tumor cells already express high levels of uPAR (55). Thus, we sought to test the role of uPAR on the regulation of ␣5␤1/Fnmediated signaling in tumor cells expressing uPAR.…”

Section: Resultsmentioning

confidence: 99%

Urokinase Receptors Are Required for α5β1 Integrin-mediated Signaling in Tumor Cells

Wei

Tang

Kim

et al. 2007

Journal of Biological Chemistry

101

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Up-regulation of urokinase receptors is common during tumor progression and thought to promote invasion and metastasis. Urokinase receptors bind urokinase and a set of ␤1 integrins, but it remains unclear to what degree urokinase receptor/ integrin binding is important to ␤1 integrin signaling. Using site-directed mutagenesis, single amino acid mutants of the urokinase receptor were identified that fail to associate with either ␣3␤1 (D262A) or ␣5␤1 (H249A) but associate normally with urokinase. To study the effects of these mutations on ␤1 integrin function, endogenous urokinase receptors were first stably silenced in tumor cell lines HT1080 and H1299, and then wild type or mutant receptors were expressed. Knockdown of urokinase receptors resulted in markedly reduced fibronectin and ␣5␤1-dependent ERK activation and metalloproteinase MMP-9 expression. Re-expression of wild type or D262A mutant receptors but not the ␣5␤1 binding-deficient H249A mutant reconstituted fibronectin responses. Because urokinase receptor⅐␣5␤1 complexes bind in the fibronectin heparin-binding domain (Type III 12-14) whereas ␣5␤1 primarily binds in the RGD-containing domain (Type III 7-10), signaling pathways leading to ERK and MMP-9 responses were dissected. Binding to III 7-10 led to Src/focal adhesion kinase activation, whereas binding to III 7-14 caused Rac 1 activation. Tumor cells engaging fibronectin required both Type III 7-10-and 12-14-initiated signals to activate ERK and up-regulate MMP-9. Thus urokinase receptor binding to ␣5␤1 is required for maximal responses to fibronectin and tumor cell invasion, and this operates through an enhanced Src/Rac/ERK signaling pathway.The urokinase receptor (uPAR), 3 a glycosylphosphatidylinositol-anchored membrane protein, has been shown to initiate signal transduction and regulate cell proliferation, adhesion, migration, and invasion (1-4). The expression of uPAR on tumor cells strongly correlates with their migratory and invasive phenotype (5-8). Down-regulation of uPAR expression by antisense or RNAi strategies inhibits tumor invasion and metastasis of various cancer types (8 -12). But because uPAR has multiple functions, the mechanisms underlying its influence on tumor cell invasion remain incompletely defined.One mechanism by which uPAR is reported to influence cellular behavior is by associating with signaling molecules and initiating signal transduction (3, 13-15). As uPAR lacks both transmembrane and cytoplasmic domains, uPAR-mediated signaling is thought to require transmembrane partners, particularly integrins (3,16,17) and tyrosine kinase receptors such as platelet-derived growth factor receptor and EGFR (18 -21). uPAR has been shown to associate with ␤1, ␤2, ␤3, and ␤5 integrins (17,(22)(23)(24). The uPAR binding sites on ␤1 integrins have been identified (25-27); both domains II and III of uPAR are implicated in the integrin interaction (28, 29). Recently we have shown that uPAR directly binds integrin ␣5␤1 and regulates its conformation and function (25); however, the exact signa...

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Section: Resultsmentioning

confidence: 99%

Urokinase Receptors Are Required for α5β1 Integrin-mediated Signaling in Tumor Cells

Wei

Tang

Kim

et al. 2007

Journal of Biological Chemistry

101

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“…Thus, our results demonstrating considerably elevated PAI-1 and u-PAR expression under oxidative stress conditions indicate a necessity of control of the fibrinolytic system in these pathological states. High-plasma PAI-1 concentrations may lead to an increase in the deposition of fibrin and subsequent formation of a thrombus (Kohler and Grant 2000), whereas the u-PA and its receptor are known to be the agents participating in the pathogenesis of cancer (Alfano et al 2005;de Bock and Wang 2004).…”

Section: Discussionmentioning

confidence: 99%

Effect of oxidative stress on the expression of t-PA, u-PA, u-PAR, and PAI-1 in endothelial cells

Oszajca

Bieniasz

Brown

et al. 2008

Biochem. Cell Biol.

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In this study we examined the effects of exogenous nitric oxide (sodium nitroprusside, SNP) and hydrogen peroxide (H2O2) on the expression level of tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), and plasminogen activator inhibitor type 1 (PAI-1) in human umbilical vein endothelial cells (HUVEC). The expression of selected genes involved in fibrynolysis under the influence of oxidative stress was analyzed at the levels of mRNA, protein, and promoter activity. The results of the conducted studies revealed that oxidative stress in endothelial cells causes a significant increase in PAI-1 and u-PAR expression and a moderate increase in t-PA and u-PA expression at all of the investigated levels. We attempted to elucidate the molecular signaling mechanisms by which SNP and H2O2 regulate expression of the respective fibrinolytic factors. Therefore, we tested the protein levels of AP-1, NF-kappaB, and HIF-1 and their DNA-binding activity in endothelial cells subjected to oxidative stress. We found strong correlation between AP-1, NF-kappaB, and HIF-1 in the contribution of regulation of selected genes. In addition, we also found that the inhibition of PAI-1 synthesis by antisense oligonucleotide to PAI-1 mRNA results in markedly increased u-PAR expression and that NF-kappaB and AP-1 are involved in this regulation.

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“…The uPA system consists of uPA, uPAR, plasminogen, and plasminogen activator inhibitor [18]. In vitro studies have shown that suPAR is associated with cell adhesion, migration, and proliferation [19,20].…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Significance of Soluble Urokinase Plasminogen Activator Receptor in Acute Myeloid Leukemia

Erkut¹,

Menteşe²,

Özbaş³

et al. 2016

Tjh

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Objective:The soluble urokinase plasminogen activator receptor (suPAR) is a soluble form of the urokinase plasminogen activator receptor expressed in various immune and cancer cells. The levels of suPAR have been demonstrated to correlate with prognosis in various cancers. This study was intended to investigate serum suPAR levels and their effect on prognosis in patients with acute myeloid leukemia (AML).Materials and Methods:Thirty newly diagnosed patients with AML and 29 healthy individuals were enrolled. Serum suPAR levels were analyzed by enzyme-linked immunosorbent assay.Results:Serum suPAR levels were significantly higher in patients with AML than in healthy individuals (9±5.9 ng/mL and 2.4±1.4 ng/mL, respectively; p<0.001). Positive correlation was determined between suPAR levels and white blood cell counts (p<0.01). Serum suPAR levels were lower in patients who achieved complete response than in patients not achieving complete response (5.5±2.2 ng/mL and 12±6.6 ng/mL, respectively; p<0.001). The median overall survival was longer in patients with serum suPAR levels below 6.71 ng/mL than in those with serum suPAR levels above 6.71 ng/mL (12.6±13.2 months and 1.71±0.6 months, respectively; p=0.02). Multivariate Cox regression analysis showed that suPAR had independent prognostic value (95% confidence interval: 1.029-6.259; p<0.05) in AML.Conclusion:Serum suPAR levels can be used as a prognostic marker in AML.

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Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

Cited by 136 publications

References 110 publications

Urokinase Receptors Are Required for α5β1 Integrin-mediated Signaling in Tumor Cells

Urokinase Receptors Are Required for α5β1 Integrin-mediated Signaling in Tumor Cells

Effect of oxidative stress on the expression of t-PA, u-PA, u-PAR, and PAI-1 in endothelial cells

The Prognostic Significance of Soluble Urokinase Plasminogen Activator Receptor in Acute Myeloid Leukemia

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