Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of urokinase-type plasminogen activator (u-PA) to a specific cell surface receptor (uPA-R) has been shown to enhance plasminogen activation, a process involved in extracellular matrix degradation and cell migration during angiogenesis and tumor growth. We investigated the expression of u-PA and uPA-R in renal cell carcinomas (n = 11). By immunohistochemistry using monoclonal and polyclonal anti-uPA-R antibodies, we found that tumoral capillary endothelial cells (von Willebrand factor and CD31 positive cells) overexpressed uPA-R, whereas vascular endothelial cells of the normal human kidney do not. In addition, tumor-associated macrophages (CD68-positive cells) strongly expressed uPA-R. In contrast, few tumoral cells and stromal fibroblasts expressed uPA-R. By in situ hybridization using a cDNA S35-labeled probe specific for uPA-R, we confirmed the local expression of uPA-R messenger RNA. We also detected the induction of u-PA in tumoral capillary endothelial cells and in tumor-associated macrophages. In two cases, tumoral cells themselves were also stained by anti-u-PA antibodies in focal areas. Finally tissue-type plasminogen activator (t-PA) was also overexpressed by tumoral capillary endothelial cells as compared with endothelial cells of normal human kidney vessels. These findings indicate an active invasive phenotype of endothelial cells in renal cell carcinoma and suggest a role for the plasminogen activation system in tumoral angiogenesis and invasion.
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PMID:Endothelial and macrophage upregulation of urokinase receptor expression in human renal cell carcinoma. 902 4

We examined the role of urokinase-type plasminogen activator (u-PA) in the metastasis of the human renal cell carcinoma (HRCC) implanted in athymic nude mice. Cells from a HRCC KG-2 line were implanted in orthotopic (kidney) and ectopic (subcutaneous) organs. The KG-2 cells implanted in the kidney produced local tumors and lung metastases, whereas those implanted subcutaneously produced only local tumors. The production of u-PA was determined by immunohistochemistry and an enzyme-linked immunosorbent assay (ELISA). High levels of u-PA were produced by the metastatic kidney tumors and lung metastases, whereas the subcutaneous tumors produced low levels. KG-2 cells co-cultured with mouse kidney or lung fibroblasts produced higher levels of u-PA than KG-2 cells co-cultured with mouse skin fibroblasts. Furthermore, KG-2 cells cultured with the conditioned medium from mouse kidney or lung fibroblasts produced higher levels of u-PA than KG-2 cells cultured with the conditioned medium from mouse skin fibroblasts. The results indicate that the expression of u-PA by KG-2 cells is one of the important factors that determine their metastatic potential and that the production of u-PA is influenced by the organ microenvironment, including soluble factors produced by surrounding fibroblasts.
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PMID:Organ-site dependence for the production of urokinase-type plasminogen activator and metastasis by human renal cell carcinoma cells. 940 16

Malignant tumors contrast with benign ones in their ability to invade adjacent tissue and to metastasize. The urokinase plasminogen activator is a proteolytic enzyme that can facilitate these processes. In many carcinomas, the concentration of the urokinase plasminogen activator system is high. The high expression of these enzymes is related to tumor grade. In this study, we have investigated whether secretion of the urokinase plasminogen activator, urokinase plasminogen activator receptor, and plasminogen activator inhibitor 1 in normal kidney tissue and kidney cancer tissue follows this pattern. We have found that urokinase plasminogen activator, urokinase plasminogen activator receptor, and plasminogen activator inhibitor 1 were expressed in higher levels in kidney cancers (squamous cell carcinoma and renal cell carcinoma) than in normal kidney tissue and that these differences were statistically significant (P < or = 0.05). In renal cell carcinomas, we have observed differences between normal kidney tissue and renal cell carcinomas in males and Caucasians but not in females and African Americans (P < or = 0.05). Expression of the urokinase plasminogen activator system was also higher in grade III tumors when compared with lower-grade tumors or normal tissue.
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PMID:Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype. 956 80

The urokinase-type plasminogen activator (uPA) system plays an important role in tumor cell invasion, metastases, and angiogenesis. uPA, uPA receptor, and plasminogen activator inhibitor 1 (PAI-1) are prognostic factors in different solid tumors, e.g., renal cell carcinomas (RCCs). von Hippel-Lindau (VHL) disease is an inherited cancer syndrome that is characterized by extensively vascularized tumors, including hemangioblastomas and RCCs. In 75% of sporadic RCCs, the VHL gene is also inactivated. It has been recognized in sporadic RCC that PAI-1 mRNA levels are up-regulated and uPA mRNA levels are down-regulated. We determined the role of the VHL tumor suppressor gene in the regulation of the uPA system in RCC. In 786-O RCC cells expressing the wild-type (wt) VHL gene, we measured a 3-fold higher overall urokinase activity than in 786-O cells expressing a mutant VHL gene or lacking VHL. uPA mRNA and protein levels were higher in cells with wt VHL compared with cells with mutant VHL or lacking VHL. In addition, PAI-1 mRNA and protein levels were dramatically increased in 786-O cells with mutant VHL or lacking VHL, compared with cells expressing wt VHL. Our results provide further evidence that the VHL gene plays an important role in the process of angiogenesis by regulation of plasmin-mediated proteolysis of the extracellular matrix and may explain why VHL-induced RCCs grow slowly and metastasize relatively late.
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PMID:Regulation of the urokinase-type plasminogen activator system by the von Hippel-Lindau tumor suppressor gene. 1048 95

Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cytotoxic chemotherapeutic agents. Although often responsive to immunomodulatory agents including interleukin 2 and IFN-alpha, the overall results in randomized Phase III studies are disappointing with only modest improvements in overall survival. This Phase II study evaluated the efficacy and tolerability of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inoperable RCC. Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks (one cycle). This was repeated in patients with stable disease (StD), but was discontinued after 16 weeks if there was no evidence of an objective response. Because minimal toxicity was seen, subsequent patients (n = 20) were treated until progressive disease (PD) was documented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 months, and the remainder had PD. Median overall survival was 7.3 months. Duration of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrogate serum/plasma (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase plasminogen activator soluble receptor (uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a poor prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantly after one cycle in patients with PD but not in those with StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF levels were significantly higher in PD patients compared with StD patients before and/or after 1 cycle of treatment. In conclusion, razoxane is an antiangiogenic agent that has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC. Surrogate serum and urinary markers of angiogenesis may have a role to play in predicting disease response and overall survival in RCC.
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PMID:A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis. 1115 22

Two renal cell carcinoma cell lines (49RC 43STR and 75RC 2STR) were characterized by detection of the cell surface proteins: CD44(var), intercellular adhesion molecule-1 (ICAM-1), urokinase-type plasminogen activator (uPA) and its receptor and aminopeptidase N (APN). To detect their localization the immunoluminescent technique was used. In addition, the enzyme activity of uPA and APN was investigated in cell suspensions as well as in monolayers. The latter procedure was more advantageous since the additional use of HPLC permits a single registration of the fluorescent hydrolysis-product AMC (7-amino-4-methylcoumarin) without interference by cellular autofluorescence or non-reacted fluorescent substrate. Unlike 75RC 2STR, the cell line 49RC 43STR expressed high levels of uPA and APN. Contrary to that the cell line 75RC 2STR expressed high levels of ICAM-1 and CD44(v6), whereas 49RC 43STR showed a low level of ICAM-1 and no distinct light signal with anti-CD44(v6). The uPA activity was measured directly as well as indirectly (via plasmin) with the substrate Z-Gly-Gly-Arg-AMC. Both activator and plasmin activity were inhibited by D-Val-Phe-Lys-CMK and phenylmethylsulfonyl fluoride. The anti-catalytic antibody to uPA and that to uPA receptor were found to be inhibiting the uPA activity in a concentration-dependent manner. APN activity was assayed using alanine-p-nitroanilide. Peptidase activity was effectively inhibited by 1,10-phenanthroline and partly inhibited by ethylenediamine-tetraacetic acid.
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PMID:Cell surface antigens in renal tumour cells: detection by immunoluminescence and enzymatic analysis. 1155 47

Protein C inhibitor (PCI), a member of the serine protease inhibitor family, is produced in various human tissues, including the liver, kidney and testis. In addition to inhibiting the anticoagulant protein C pathway, PCI also inhibits urinary plasminogen activator (uPA), which is a well-known mediator of tumor cell invasion. In the present study, to clarify the biologic significance of PCI in the kidney, we compared the expression of PCI between human renal cell carcinoma (RCC) tissue and nontumor kidney tissue. The PCI antigen level in RCC tissue was found to be significantly lower than in nontumor kidney tissue, and expression of PCI mRNA was detected in normal renal proximal tubular epithelial cells (RPTEC), but not in RCC or in an RCC cell line (Caki-1 cells). No differences were detected between the nucleotide sequence of the major cis-elements in the promoter region of the PCI gene from nontumor kidney and RCC tissues, RPTEC and Caki-1 cells, an RPTEC-derived RCC cell line. The in vitro invasiveness of Caki-1 cells transfected with a PCI expression vector was significantly decreased compared to mock-transfected Caki-1 cells, and it was blocked in the presence of anti-PCI antibody. Since PCI itself did not affect the proliferation rate of Caki-1 cells or cell expression of uPA in vitro, the effect of uPA, PCI, heat-inactivated PCI and plasminogen activator inhibitor (PAI)-1 on the invasive potential of cultured RCC cells was evaluated. The in vitro invasiveness of Caki-1 cells, which express uPA, was significantly enhanced by the addition of uPA, and it was inhibited by anti-uPA antibody, PCI and PAI-1, but not by heat-inactivated PCI. In addition, uPA activity was significantly decreased and uPA-PCI complex level was significantly increased in the culture medium of PCI expression vector-transfected Caki-1 cells as compared to mock-transfected Caki-1 cells. These findings strongly suggest that PCI regulates the invasive potential of RCC cells by inhibiting uPA secreted by these cells. The results of our study suggest that PCI might be a potential therapeutic agent for inhibiting renal tumor invasion.
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PMID:Regulation of carcinoma cell invasion by protein C inhibitor whose expression is decreased in renal cell carcinoma. 1469 15

The urokinase-type plasminogen activator (uPA) system plays a central role in extracellular matrix degradation, cell migration, and invasion. uPA belongs to the family of serine proteases. It has been shown that its proteolytic activity is involved in the metastatic process by activation and binding to its receptor (uPAR). Previous studies in several organ systems have elucidated a higher uPA expression in malignant tissue in comparison to normal tissue. In this study uPA and uPAR gene expression were investigated in 18 human renal cell carcinoma (RCC) specimens in comparison with adjacent non-malignant renal tissues. mRNA in situ hybridisation and immunohistochemical staining were performed. mRNA of uPA and uPAR was significantly higher expressed in 56% (10/18) and 72% (13/18) of the RCC specimens in comparison to the adjacent non-malignant renal tissue (p<0.0001), respectively. uPA-mRNA and uPAR-mRNA were expressed predominantly in malignant renal cells and in very few surrounding stromal cells. The elevated expression of uPAR-protein in RCC reached statistical significance compared to adjacent normal tissue (p=0.007). uPAR genes were higher expressed in comparison to uPA alone. There was a statistical trend that higher expression of uPA and uPAR corresponded with TNM tumour stage and grade in RCC. Further investigations need to be done with larger sample sizes to prove a correlation of expression between uPA and uPAR to a more aggressive phenotype. We conclude that uPA- and uPAR are overexpressed in RCC and could function as tumour markers.
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PMID:Differential gene expression of urokinase-type plasminogen activator and its receptor in human renal cell carcinoma. 1607 91

Fibrinolytic factors have an important role in tumor progression through the degradation of extracellular matrix. The increased levels of urokinase-type plasminogen activator (uPA), uPA-receptor (uPAR) and type-1 PA inhibitor (PAI-1) are reported in human renal cell carcinoma (RCC). Connexin (Cx) gene, a member of gap junction, is known to act as a tumor suppressor gene. We have reported that Cx32 improves malignant phenotypes of metastatic RCC cells via the inhibition of Src-dependent signaling. In this study, we examined the effect of expression of Cx32 gene on the production of uPA, uPAR and PAI-1, and on the induction of PAI-1 stimulated by hypoxia in a human metastatic RCC cell line, Caki-1 cells. Cx32 expression decreased both mRNA level and production of PAI-1, uPA and uPAR in Caki-1 cells. Cx32 also decreased hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha mRNA level. PP1, a Src inhibitor, significantly decreased PAI-1, uPA, uPAR and HIF-alpha mRNA levels in Caki-1 cells. Furthermore, Cx32 suppressed the induction of HIF-2alpha protein in Caki-1 cells under hypoxia. PAI-1 mRNA level in Cx32-transfected Caki-1 cells was lower than that of mock transfectant under hypoxic conditions. These results suggest that Cx32 might reduce PAI-1, uPA and uPAR production in metastatic RCC cells via the inhibition of Src-dependent induction of HIF-1alpha and HIF-2alpha gene expression and that Cx32 might suppress hypoxia-inducible gene expression under hypoxic conditions.
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PMID:Connexin 32 down-regulates the fibrinolytic factors in metastatic renal cell carcinoma cells. 1628 36

Activated protein C (APC) and protein C inhibitor (PCI) are the major components of the anticoagulant protein C pathway. Recently, APC and PCI have been demonstrated to play many roles not only in the regulation of hemostasis but also in cell inflammation, proliferation, apoptosis, tumor cell migration, invasion, and metastasis. Here we summarize the role of APC and PCI in malignancy. APC increases migration of ovarian cancer cells and choriocarcinoma cells in a Transwell invasion assay in the presence of plasminogen activator inhibitor (PAI)-1; this finding suggests that APC stimulates urokinase-type plasminogen activator (uPA) by forming a complex with PAI-1 leading to activation of extracellular matrix proteases and increased invasion. It was recently reported that APC, independent of PAI-1, may increase invasion and chemotaxis of breast cancer cells by activating specific signaling pathways through endothelial protein C receptor (EPCR) and protease-activated receptor (PAR)-1. APC also increased proliferation of vascular endothelial cells and angiogenesis by EPCR-mediated activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and endothelial nitric oxide synthase (eNOS) pathways. On the other hand, we have previously reported that both uPA and PCI are synthesized in renal proximal tubular epithelial cells (RPTECs) and that PCI expression in RPTEC-derived tumor cells is significantly decreased compared with normal RPTECs. The RPTEC-derived renal carcinoma cell line Caki-1 also showed decreased expression of PCI. PCI inhibited in vitro invasive activity of Caki-1 and breast cancer cells by its protease inhibitory activity. However, PCI was found to inhibit the growth and metastatic potential of breast cancer cells independent of its protease inhibitory activity in severe combined immunodeficient mice. PCI can also inhibit angiogenesis in vivo and in vitro assays independent of its protease inhibitory activity. Overall, these data show that APC promotes tumor cell invasion by EPCR-mediated and PAR-1-mediated protease activity and that PCI inhibits tumor cell invasion in vitro by its protease inhibitory activity and suppresses tumor cell growth, metastasis, and angiogenesis independent of its protease inhibitory activity.
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PMID:Protein C and its inhibitor in malignancy. 1800 Jul 93


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