Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1

There is substantial evidence implicating the urokinase system in tissue remodeling during neo-vascularization, inflammation, tumor invasion, and metastasis. Regulated degradation of the extracellular matrix at the leading edge of migrating cells, mediated by uPA and uPAR, is required for tissue remodeling, invasiveness, and angiogenesis. Psoriasis and basal cell carcinoma (BCC) are the most common skin diseases. Pathogenesis of both of them is associated with keratinocyte hyperproliferation, inflammatory cell migration, and angiogenesis-processes in which the plasminogen system (uPA, uPAR, tPA, and PAI-1) plays a crucial role. In the present study, the comparative analysis of uPA, uPAR, tPA, and PAI-1 expression in the normal skin, in the biopsies of patients with psoriasis vulgaris, and BCC was carried out. uPA, uPAR, and PAI-1 expression was up-regulated in the epidermis of psoriatic skin and in tumor cells in BCC. Increased uPAR expression was detected in the derma of psoriatic lesions and in the stroma surrounding tumor cells in BCC. Increased expression of uPA in epidermal cells in psoriasis and in tumor cells in BCC suggests an important role of the uPA system for aggressively proliferating and invading cells of epidermal origin. A possible activation of the stroma, as a result of uPA-uPAR interaction between tumor cells and the surrounding stroma, is suggested.

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“…These data were confirmed clinically: it was found that human differentiated keratoacanthomas expressed low levels of uPAR [47].…”

Section: Discussionsupporting

confidence: 55%

Increased expression of uPA, uPAR, and PAI-1 in psoriatic skin and in basal cell carcinomas

et al. 2017

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“…Urokinase-type plasminogen activator receptor (uPAR) is a component of the plasminogen activator (PA) system. This system plays an important role in many physiological and pathological processes, including tissue remodelling [ 8 ], thrombosis [ 9 ], inflammation [ 10 ], and tumourigenesis [ 11 ]. The soluble form of uPAR (suPAR) can be detected in serum and other organic fluids [ 12 ]; its levels are increased in patients with HIV infection, malaria, tuberculosis, and sepsis, suggesting that it could serve as a useful prognostic biomarker [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Serum suPAR and syndecan-4 levels predict severity of community-acquired pneumonia: a prospective, multi-centre study

Luo

Zheng

et al. 2018

Crit Care

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BackgroundCommunity-acquired pneumonia (CAP) is a major cause of death worldwide and occurs with variable severity. There are few studies focused on the expression of soluble urokinase-type plasminogen activator receptor (suPAR) and syndecan-4 in patients with CAP.MethodsA prospective, multi-centre study was conducted between January 2014 and December 2016. A total of 103 patients with severe CAP (SCAP), 149 patients with non-SCAP, and 30 healthy individuals were enrolled. Clinical data were recorded for all enrolled patients. Serum suPAR and syndecan-4 levels were determined by quantitative enzyme-linked immunosorbent assay. The t test and Mann–Whitney U test were used to compare between two groups; one-way analysis of variance and the Kruskal–Wallis test were used to compare multiple groups. Correlations were assessed using Pearson and Spearman tests. Area under the curve (AUCs), optimal threshold values, sensitivity, and specificity were calculated. Survival curves were constructed and compared by log-rank test. Regression analyses assessed the effect of multiple variables on 30-day survival.ResultssuPAR levels increased in all patients with CAP, especially in severe cases. Syndecan-4 levels decreased in patients with CAP, especially in non-survivors. suPAR and syndecan-4 levels were positively and negatively correlated with severity scores, respectively. suPAR exhibited high accuracy in predicting SCAP among patients with CAP with an AUC of 0.835 (p < 0.001). In contrast, syndecan-4 exhibited poor diagnostic value for predicting SCAP (AUC 0.550, p = 0.187). The AUC for predicting mortality in patients with SCAP was 0.772 and 0.744 for suPAR and syndecan-4, respectively; the respective prediction threshold values were 10.22 ng/mL and 6.68 ng/mL. Addition of both suPAR and syndecan-4 to the Pneumonia Severity Index significantly improved their prognostic accuracy, with an AUC of 0.885. Regression analysis showed that suPAR ≥10.22 ng/mL and syndecan-4 ≤ 6.68 ng/mL were reliable independent markers for prediction of 30-day survival.ConclusionsuPAR exhibits high accuracy for both diagnosis and prognosis of SCAP. Syndecan-4 can reliably predict mortality in patients with SCAP. Addition of both suPAR and syndecan-4 to a clinical scoring method could improve prognostic accuracy.Trial registrationClinicalTrials.gov, NCT03093220. Registered on 28 March 2017 (retrospectively registered).

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“…uPAR partitioning to lipid rafts contributes to regulate some biological activities. For example, in basal kerantinocytes, uPAR may sequester the TNF-α converting enzyme (TACE) within lipid rafts, preventing Notch1 activation, and thereby promoting cell proliferation and tumor formation [20]. In endothelial colony-forming cells (ECFCs), inhibition of uPAR expression by antisense oligonucleotides promotes disruption of caveolin-containing lipid rafts, suggesting a prominent role for uPAR in caveolae organization [21].…”

Section: Discussionmentioning

confidence: 99%

New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms

Gorrasi

Petrone

Santi

et al. 2020

Cells

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The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells is impaired by anti-uPAR antibodies, without recovery of the uPAR-independent migration mechanisms formerly active. Prostate carcinoma PC3 cells, which express high endogenous uPAR levels, migrated only through a uPAR-dependent mechanism; in fact, the silencing of uPAR expression inhibited their migration. We hypothesize a crucial role of the uPAR glycosyl-phosphatidyl-inositol (GPI) tail, which promotes uPAR partitioning to lipid rafts, in uPAR-controlled cell migration. Here, we show that removal of the uPAR GPI-tail, or lipid rafts disruption by methyl-beta-cyclodextrin impairs migration of PC3 cells, incapable of uPAR-independent migration, whereas it restores uPAR-independent migration in uPAR-293 cells. We then show that, in PC3 cells, both uPAR signaling partners, β1 integrins and receptors for formylated peptides (FPRs), partly associate with lipid rafts. Inhibition of their interaction with uPAR impairs this association and impairs cell migration. Interestingly, blocking uPAR association with FPRs also impairs β1 integrin partitioning to lipid rafts, whereas blocking its association with β1 integrins has no effect on FPRs partitioning. On these bases, we propose that uPAR controls cell migration by connecting β1 integrins and FPRs and, through its GPI tail, by driving them into lipid rafts, thus promoting pro-migratory signals. uPAR-mediated partitioning of integrins to lipid rafts is strictly dependent on uPAR association with FPRs.

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Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1

Cited by 12 publications

References 57 publications

Increased expression of uPA, uPAR, and PAI-1 in psoriatic skin and in basal cell carcinomas

Increased expression of uPA, uPAR, and PAI-1 in psoriatic skin and in basal cell carcinomas

Serum suPAR and syndecan-4 levels predict severity of community-acquired pneumonia: a prospective, multi-centre study

New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms

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