Beschreibung:
<jats:title>Abstract</jats:title><jats:p>The urokinase‐type plasminogen activator (<jats:styled-content style="fixed-case">uPA</jats:styled-content>) receptor (<jats:styled-content style="fixed-case">uPAR</jats:styled-content>) focuses <jats:styled-content style="fixed-case">uPA</jats:styled-content> proteolytic activity on the cell membrane, promoting localized degradation of extracellular matrix (<jats:styled-content style="fixed-case">ECM</jats:styled-content>), and binds vitronectin (<jats:styled-content style="fixed-case">VN</jats:styled-content>), mediating cell adhesion to the <jats:styled-content style="fixed-case">ECM</jats:styled-content>. <jats:styled-content style="fixed-case">uPAR</jats:styled-content>‐bound <jats:styled-content style="fixed-case">uPA</jats:styled-content> and <jats:styled-content style="fixed-case">VN</jats:styled-content> induce proteolysis‐independent intracellular signalling, regulating cell adhesion, migration, survival and proliferation. <jats:styled-content style="fixed-case">uPAR</jats:styled-content> cross‐talks with <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4, the receptor for the stroma‐derived factor 1 chemokine. <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4 is crucial in the trafficking of hematopoietic stem cells from/to the bone marrow, which involves also <jats:styled-content style="fixed-case">uPAR</jats:styled-content>. Both <jats:styled-content style="fixed-case">uPAR</jats:styled-content> and <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4 are expressed in acute myeloid leukaemia (<jats:styled-content style="fixed-case">AML</jats:styled-content>), 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 <jats:styled-content style="fixed-case">uPAR</jats:styled-content> and <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4 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 <jats:styled-content style="fixed-case">uPAR</jats:styled-content> and <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4 in <jats:styled-content style="fixed-case">AML</jats:styled-content> cell lines. Indeed, these miRs directly target the 3′untranslated region of both <jats:styled-content style="fixed-case">uPAR</jats:styled-content>‐ and <jats:styled-content style="fixed-case">CXCR</jats:styled-content>4‐<jats:styled-content style="fixed-case">mRNA</jats:styled-content>s; accordingly, <jats:styled-content style="fixed-case">uPAR</jats:styled-content>/<jats:styled-content style="fixed-case">CXCR</jats:styled-content>4 expression is reduced by their overexpression in <jats:styled-content style="fixed-case">AML</jats:styled-content> 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 <jats:styled-content style="fixed-case">uPAR</jats:styled-content>/<jats:styled-content style="fixed-case">CXCR</jats:styled-content>4 expression and miR‐146a and miR‐335 levels in <jats:styled-content style="fixed-case">AML</jats:styled-content> blasts, suggesting their possible role in the regulation of <jats:styled-content style="fixed-case">uPAR</jats:styled-content>/CXCR4 expression also <jats:italic>in vivo</jats:italic>.</jats:p>