Adenovirus E1A orchestrates the urokinase-plasminogen activator system and upregulates PAI-2 expression, supporting a tumor suppressor effect
V. Fernández‐SoriaMatilde E. LleonartMaría Díaz-FuertesRaquel VilluendasRicardo Sánchez‐PrietoÀngels FabraSantiago Ramón y Cajal
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Invasiveness and metastatic potential are the two most important properties defining malignancy. The adeno-virus E1A (Ad-E1A) gene has a dual effect as a proliferative gene and as a tumor-suppressor gene, decreasing tumor growth and the metastatic potential of malignant cells. In order to study genes related with the antimetastatic effect of Ad-E1A in human cells, we performed a microarray analysis using OncoChiptrade mark. In three independent experiments, NIH3T3, IMR90 and MDA MB 435 cells were infected with pLPC retroviruses carrying the adenovirus 12S E1A gene or the GFP gene. We analyzed cDNA expression by using the CNIO OncoChipTM, a cDNA microarray containing a total of 6386 genes represented by 7237 clones. uPA, uPAr, tPA, PAI-1 and PAI-2 were also studied at RNA and protein levels. Microarrays of cDNA expression, RT-PCR and Western blot performed in IMR90 E1A-expressing cells showed downregulation of uPA, uPAr, tPA, PAI-1 and upregulation of PAI-2. These results were confirmed in NIH3T3 and MDA MB 435 breast carcinoma cells, with PAI-2 upregulation by RT-PCR and Western blot. In addition, zymographic analysis demonstrated that E1A expression greatly reduced the gelatinase activity of the pro-MMP2 and -MMP9 proteins. We propose that adenovirus E1A may orchestrate the expression of most members of the urokinase-plasminogen activation system, downregulating potentially invasive genes and upregulating PAI-2, which is associated with a better prognosis in human tumors.183 Background: New biomarkers are warranted to distinguish between indolent and aggressive prostate cancer (PCa). The urokinase plasminogen activator receptor (uPAR) plays an important role in pericellular proteolysis by binding urokinase plasminogen activator (uPA). This is required for degradation of the extracellular matrix and for cancer invasion. In addition to binding uPAR, uPA cleaves uPAR liberating uPAR(I) and uPAR(II-III). Intact, uPAR(I-III), and uPAR(II-III) can be liberated from the cell surface resulting in three different uPAR forms in circulation. The different uPAR forms are strong prognostic markers in several cancers. We measured the uPAR forms in plasma from patients with different stages of PCa. Methods: Between February 1, 2012 and October 1, 2014, 400 patients with PCa (se table) had plasma samples obtained. The levels of intact uPAR [uPAR(I-III)], intact uPAR + cleaved uPAR domains II+III [uPAR(I-III) + uPAR(II-III)], and cleaved uPAR domain I [uPAR(I)] were determined in citrated plasma samples with two-site sandwich time-resolved fluorescence immunoassays (TR-FIAs). Results: Plasma uPAR(I-III) + uPAR(II-III) and uPAR(I) were significantly higher in hormone naïve patients and CRPC patients compared to patients with localized disease (see table). Quantification of intact uPAR(I-III) revealed no significant differences between the three groups. Conclusions: Our findings suggest that uPAR(I-III) + uPAR(II-III) and uPAR(I) are associated with higher tumor stage as well as advanced PCa disease. These associations suggest that uPAR domains in plasma harbour prognostic value for PCa patients. Further studies are warranted to validate the use of uPAR forms as biomarkers for PCa. [Table: see text]
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Objective To investigate the relationship between plasma level of urokinase-type plasminogen activator(uPA),urokinase-type plasminogen activator receptor(uPAR)and plasminogen activator inhibitor type 1(PAI-1)and ovarian cancer.Method The concentration of uPA,uPAR and PAI-1 in 52 patients with ovarian cancer and 30 healthy subjects were simultaneously determined by ELISA.Results There were significant differences for uPA and uPAR in different grades of the patients with ovarian cancer(P0.01).However,there was no significant difference for PAI-1 in ovarian cancer patients with different grades.There were significant differences in PAI-1,uPA,uPAR between the patients with ovarian cancer and healthy subjects(P0.01).Conclusion uPA,uPAR and PAI-1 may play important roles and be used as the parameters for progression and reimplantation of ovarian malignant cancer cells.
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The cellular receptor for urokinase, uPAR, localizes its ligand, uPA, and thereby the plasminogen activation, to the cell surface. uPA also cleaves uPAR, liberating the ligand-binding domain I, and thereby inactivates the binding potential of uPAR for both uPA and vitronectin. The uPA-catalyzed cleavage of uPAR is fast on the cell surface, when uPA is bound to a neighboring uPAR molecule. uPAR can be shed from the cell surface. However, the soluble form cannot be cleaved by uPA. Glycolipid-anchored and soluble forms of intact, uPAR(I-III), and cleaved receptor, uPAR(II-III) and uPAR(I), have been identified in tissue and body fluids. It is well-established, that the total amount of all uPAR forms is a strong prognostic marker in different types of cancer. Using immunoassays, measuring the individual uPAR forms, has revealed that the cleaved uPAR forms are even stronger prognostic markers and have diagnostic utility. This review will focus on the mechanism of uPAR cleavage and the functional consequences, as well as the clinical applicability of cleaved uPAR forms.
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Objectives To study the expressions of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in the gliomas, and to analysis the relationship between uPA and uPAR expressions and the grade of human gliomas. Methods The levels of uPA and uPAR protein expressions were determined by immunohistochemical technique in 58 cases of the gliomas and 10 samples of the normal brain tissue. Results The expressions of uPA and uPAR were not detected in normal brain tissures, and positively correlated with the pathological grade of the gliomas (P0.01). Conclusions The high levels of uPA and uPAR expressions may reflect a malignant biological behavior of the glioma cells.
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To investigate the pathogenesis of unknown nosebleed patients.The ELISA test were used to detected plasma Urokinase-type plasminogen activator (uPA) and Urokinase-type plasminogen activator receptor (uPAR) level in 19 cases unknown factor nosebleed patients and 36 health persons.The results showed uPAR and uPA level in nosebleed group (before treatment) uPAR (0.14 +/- 0.04) microg/L, uPA (0.24 +/- 0.09) microg/L; (after treatment) uPAR (0.08 +/- 0.02) microg/L, uPA (0.18 +/- 0.07) microg/L. And normal group uPAR (0.07 +/- 0.03) microg/L, uPA (0.17 +/- 0.05) microg/L. The uPAR and uPA level in nosebleed group before treatment is higher than that in normal group (P <0.05). There is no significant difference between nosebleed group after treatment and normal group (P>0.05).The reasons of uPAR and uPA level high in unknown factor nosebleed patients were not clear, maybe relation to vascular endothelial cell, smooth muscle cell and neutrophil-monocytic release more uPAR and uPA. So uPAR and uPA density of nostril accumulation is more high in its microenvironment, that fibrinolytic system activated increase and result in its hyperactivity, and happened nosebleed when blood be in hypocoagulable state.
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Journal Article Intermolecular Contact Regions in Urokinase Plasminogen Activator Receptor Get access Olin D. Liang, Olin D. Liang Search for other works by this author on: Oxford Academic PubMed Google Scholar Khalil Bdeir, Khalil Bdeir Search for other works by this author on: Oxford Academic PubMed Google Scholar Rachel L. Matz, Rachel L. Matz Search for other works by this author on: Oxford Academic PubMed Google Scholar Triantafyllos Chavakis, Triantafyllos Chavakis Search for other works by this author on: Oxford Academic PubMed Google Scholar Klaus T. Preissner Klaus T. Preissner Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Biochemistry, Volume 134, Issue 5, November 2003, Pages 661–666, https://doi.org/10.1093/jb/mvg190 Published: 01 November 2003
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Abstract We investigated whether the expression levels of urokinase‐type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor‐1 (PAI‐1) correlate with clinicopathological features of oral squamous cell carcinoma (SCC). We immunohistochemically examined the expression levels of uPA, uPAR, and PAI‐1 in 160 biopsy specimens of oral SCC. Positive stainings for uPA, uPAR, and PAI‐1 were observed mainly in SCC cells, and their intensity and number of positive cells were related to lymph node involvement ( p < 0.001, p < 0.001, and p < 0.001, respectively). The expression levels of uPA and uPAR were also related to the pattern of invasion ( p < 0.05 and p < 0.001, respectively), while both were associated with tumor size ( p < 0.05). Moreover, a poor survival rate was related to the expression of uPAR ( p < 0.01) and PAI‐1 ( p < 0.05). These findings suggest that the uPA system may regulate the invasion and metastasis of oral SCC cells.
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Urokinase plasminogen activator (uPA) cleaves its three-domain cell surface receptor, uPAR, liberating domain I [uPAR(I)] and leaving the cleaved uPAR(II-III) on the cell surface. Both intact and cleaved uPAR can be shed from the cell surface. uPAR(I) was previously shown to be a prognostic factor in lung tumour extracts. Here we analyse uPAR forms in blood from patients with non-small cell lung cancer (NSCLC). Preoperatively sampled plasma/serum from 32 patients with NSCLC was analysed. Three time-resolved fluoroimmunoassays (TR-FIAs) measuring intact uPAR(I-III) (TR-FIA 1), uPAR(I-III) + uPAR(II-III) (TR-FIA 2) and uPAR(I) (TR-FIA 3) were applied. The Spearman rank correlations between plasma and serum levels of uPAR(I-III), uPAR(I-III) + uPAR(II-III), and uPAR(I) were 0.89, 0.94 and 0.68 respectively. Survival analysis demonstrated that high levels of all uPAR forms were associated with shorter survival. Adjusted for histological subtype high plasma uPAR(I-III) and uPAR(I) levels as well as serum uPAR(I) levels were significantly associated with shorter OS (hazards ratios = 4.3, 2.8 and 3.8 respectively). High blood levels of intact uPAR and its cleaved forms are associated with poor prognosis in NSCLC.
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10518 Background: The plasminogen activation system is involved in extracellular proteolysis during cancer invasion. In addition to the generation of plasminogen, urokinase (uPA) can cleave its cellular three-domain receptor, uPAR(I-III), between domain I and II, liberating domain I, uPAR(I), and leaving uPAR(II-III) on the cell surface. Both uPAR(I-III) and uPAR(II-III) can be shed from the cell. Recently, we found that high levels of both intact uPAR and its cleaved forms in blood from a small number (n = 32) of patients operated for non-small cell lung cancer (NSCLC) were associated with short overall survival (OS). The aim of the study was to investigate the prognostic impact of uPAR forms in serum from 171 NSCLC patients. Methods: Serum sampled preoperatively was available from 171 patients radically resected for NSCLC. uPAR(I-III), uPAR(I-III) plus uPAR(II-III) and uPAR(I) were measured by time-resolved fluoroimmunoassays. Results: High serum levels of each of the three uPAR forms were associated with short OS. In a multivariate survival analysis uPAR(l-lll) and uPAR(l) remained significant prognostic parameters independently of stage, histology, age, performance status and therapy, uPAR(l-lll) being the strongest (hazard ratio [HR] = 2.3, confidence interval [CI]: 1.2-4.5, p = 0.015). Conclusions: This retrospective study validate a previous study and shows that uPAR(l-lll) and uPAR(l) in serum are independent prognostic factors in patients radically operated for NSCLC. No significant financial relationships to disclose.
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