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Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells

The urokinase-type plasminogen activator (uPA) receptor (uPAR) focuses uPA proteolytic activity on the cell membrane, promoting localized degradation of extracellular matrix (ECM), and binds vitronectin (VN), mediating cell adhesion to the ECM. uPAR-bound uPA and VN induce proteolysis-independent in...

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Autores principales: Alfano, Daniela, Gorrasi, Anna, Li Santi, Anna, Ricci, Patrizia, Montuori, Nunzia, Selleri, Carmine, Ragno, Pia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568930/
https://www.ncbi.nlm.nih.gov/pubmed/26082201
http://dx.doi.org/10.1111/jcmm.12617
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author Alfano, Daniela
Gorrasi, Anna
Li Santi, Anna
Ricci, Patrizia
Montuori, Nunzia
Selleri, Carmine
Ragno, Pia
author_facet Alfano, Daniela
Gorrasi, Anna
Li Santi, Anna
Ricci, Patrizia
Montuori, Nunzia
Selleri, Carmine
Ragno, Pia
author_sort Alfano, Daniela
collection PubMed
description The urokinase-type plasminogen activator (uPA) receptor (uPAR) focuses uPA proteolytic activity on the cell membrane, promoting localized degradation of extracellular matrix (ECM), and binds vitronectin (VN), mediating cell adhesion to the ECM. uPAR-bound uPA and VN induce proteolysis-independent intracellular signalling, regulating cell adhesion, migration, survival and proliferation. uPAR cross-talks with CXCR4, the receptor for the stroma-derived factor 1 chemokine. CXCR4 is crucial in the trafficking of hematopoietic stem cells from/to the bone marrow, which involves also uPAR. Both uPAR and CXCR4 are expressed in acute myeloid leukaemia (AML), with a lower expression in undifferentiated and myeloid subsets, and higher expression in myelomonocytic and promyelocytic subsets. We hypothesized a microRNA (miR)-mediated co-regulation of uPAR and CXCR4 expression, which could allow their cross-talk at the cell surface. We identified three miRs, miR-146a, miR-335 and miR-622, regulating the expression of both uPAR and CXCR4 in AML cell lines. Indeed, these miRs directly target the 3′untranslated region of both uPAR- and CXCR4-mRNAs; accordingly, uPAR/CXCR4 expression is reduced by their overexpression in AML cells and increased by their specific inhibitors. Overexpression of all three miRs impairs migration, invasion and proliferation of myelomonocytic cells. Interestingly, we observed an inverse relationship between uPAR/CXCR4 expression and miR-146a and miR-335 levels in AML blasts, suggesting their possible role in the regulation of uPAR/CXCR4 expression also in vivo.
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spelling pubmed-45689302015-09-17 Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells Alfano, Daniela Gorrasi, Anna Li Santi, Anna Ricci, Patrizia Montuori, Nunzia Selleri, Carmine Ragno, Pia J Cell Mol Med Original Articles The urokinase-type plasminogen activator (uPA) receptor (uPAR) focuses uPA proteolytic activity on the cell membrane, promoting localized degradation of extracellular matrix (ECM), and binds vitronectin (VN), mediating cell adhesion to the ECM. uPAR-bound uPA and VN induce proteolysis-independent intracellular signalling, regulating cell adhesion, migration, survival and proliferation. uPAR cross-talks with CXCR4, the receptor for the stroma-derived factor 1 chemokine. CXCR4 is crucial in the trafficking of hematopoietic stem cells from/to the bone marrow, which involves also uPAR. Both uPAR and CXCR4 are expressed in acute myeloid leukaemia (AML), with a lower expression in undifferentiated and myeloid subsets, and higher expression in myelomonocytic and promyelocytic subsets. We hypothesized a microRNA (miR)-mediated co-regulation of uPAR and CXCR4 expression, which could allow their cross-talk at the cell surface. We identified three miRs, miR-146a, miR-335 and miR-622, regulating the expression of both uPAR and CXCR4 in AML cell lines. Indeed, these miRs directly target the 3′untranslated region of both uPAR- and CXCR4-mRNAs; accordingly, uPAR/CXCR4 expression is reduced by their overexpression in AML cells and increased by their specific inhibitors. Overexpression of all three miRs impairs migration, invasion and proliferation of myelomonocytic cells. Interestingly, we observed an inverse relationship between uPAR/CXCR4 expression and miR-146a and miR-335 levels in AML blasts, suggesting their possible role in the regulation of uPAR/CXCR4 expression also in vivo. John Wiley & Sons, Ltd 2015-09 2015-06-16 /pmc/articles/PMC4568930/ /pubmed/26082201 http://dx.doi.org/10.1111/jcmm.12617 Text en © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Alfano, Daniela
Gorrasi, Anna
Li Santi, Anna
Ricci, Patrizia
Montuori, Nunzia
Selleri, Carmine
Ragno, Pia
Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells
title Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells
title_full Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells
title_fullStr Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells
title_full_unstemmed Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells
title_short Urokinase receptor and CXCR4 are regulated by common microRNAs in leukaemia cells
title_sort urokinase receptor and cxcr4 are regulated by common micrornas in leukaemia cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568930/
https://www.ncbi.nlm.nih.gov/pubmed/26082201
http://dx.doi.org/10.1111/jcmm.12617
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