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      Urokinase-type plasminogen activator receptor (uPAR) expression enhances invasion and metastasis in RAS mutated tumors

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          Abstract

          The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane receptor that focuses urokinase (uPA) proteolytic activity on the cell surface. Its expression is increased in many human cancers, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), and correlates with a poor prognosis and early invasion and metastasis. uPAR is able to control, through a cross-talk with tyrosine kinase receptors, the shift between tumor dormancy and proliferation, that usually precedes metastasis formation. Therefore, we investigated the role of uPAR expression in RAS mutated NSCLC and CRC cells. In this study we provided evidence, for the first time, that RAS mutational condition is functionally correlated to uPAR overexpression in NSCLC and CRC cancer cell lines and patient-derived tissue samples. Moreover, oncogenic features related to uPAR overexpression in RAS mutated NSCLC and CRC, such as adhesion, migration and metastatic process may be targeted, in vitro and in vivo, by new anti-uPAR small molecules, specific inhibitors of uPAR-vitronectin interaction. Therefore, anti-uPAR drugs could represent an effective pharmacological strategy for NSCLC and CRC patients carrying RAS mutations.

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          Most cited references32

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          Regulation of cell signalling by uPAR.

          Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process.
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            EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma.

            Urokinase plasminogen activator receptor (uPAR) activates alpha5beta1 integrin and ERK signaling, inducing in vivo proliferation of HEp3 human carcinoma. Here we demonstrate that EGFR mediates the uPAR/integrin/fibronectin (FN) induced growth pathway. Its activation is ligand-independent and does not require high EGFR, but does require high uPAR expression. Only when uPAR level is constitutively elevated does EGFR become alpha5beta1-associated and activated. Domain 1 of uPAR is crucial for EGFR activation, and FAK links integrin and EGFR signaling. Inhibition of EGFR kinase blocks uPAR induced signal to ERK, implicating EGFR as an important effector of the pathway. Disruption of uPAR or EGFR signaling reduces HEp3 proliferation in vivo. These findings unveil a mechanism whereby uPAR subverts ligand-regulated EGFR signaling, providing cancer cells with proliferative advantage.
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              Identification of the urokinase receptor as an adhesion receptor for vitronectin.

              Urokinase receptors, expressed on surfaces of many cell types, focus to the pericellular space plasminogen-dependent proteolysis important in matrix remodeling and cell movement. We now report that the urokinase receptor (uPAR) is also a high affinity (Kd < 30 nM) receptor for vitronectin. Recombinant uPAR binds vitronectin in the absence of urokinase, but vitronectin binding is promoted by concurrent receptor binding of either urokinase or fragments thereof containing its uPAR binding domain. Stable epithelial cell transfectants expressing membrane-anchored uPAR, but not cells expressing soluble uPAR, become strongly adhesive with altered morphology in the absence of urokinase. These observations identify a new class of vitronectin receptor and imply a duality in function for the receptor that intrinsically links matrix adhesion to regulation of protease activity. Increases in urokinase receptor expression known to be associated with cellular activation and malignant transformation could modulate cellular trafficking and function by promoting attachment to vitronectin.
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                Author and article information

                Contributors
                robianco@unina.it
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 August 2017
                24 August 2017
                2017
                : 7
                : 9388
                Affiliations
                [1 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Clinical Medicine and Surgery, , University of Naples “Federico II”, ; Naples, Italy
                [2 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Translational Medical Sciences, , University of Naples Federico II, ; Naples, Italy
                [3 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Molecular Medicine and Medical Biotechnologies, , University of Naples Federico II, ; Naples, Italy
                [4 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, , CEINGE Biotecnologie Avanzate S.C.aR.L, ; Naples, Italy
                [5 ]ISNI 0000 0004 1757 3729, GRID grid.5395.a, Division of Pathology, , Department of Surgery, University of Pisa, ; Pisa, Italy
                [6 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Neuroscience, , Reproductive Science and Dentistry, Division of Pharmacology, School of Medicine, “Federico II” University of Naples, ; Naples, Italy
                [7 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Pharmacy, , University of Naples Federico II, ; Naples, Italy
                [8 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Department of Public Health, , Federico II University, ; Naples, Italy
                Author information
                http://orcid.org/0000-0002-2181-8026
                http://orcid.org/0000-0002-1678-4183
                http://orcid.org/0000-0001-8697-986X
                Article
                10062
                10.1038/s41598-017-10062-1
                5571185
                28839232
                5e5e552a-4b85-4e14-981d-1f25ce86976c
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 March 2017
                : 21 July 2017
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