Open AccessUrokinase receptor and CXCR 4 are regulated by common micro RNA s in leukaemia cells
Author(s) -
Alfano Daniela,
Gorrasi Anna,
Li Santi Anna,
Ricci Patrizia,
Montuori Nunzia,
Selleri Carmine,
Ragno Pia
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12617
Subject(s) - urokinase receptor , vitronectin , microbiology and biotechnology , chemokine receptor , cancer research , cell migration , plasmin , biology , chemistry , receptor , cell , chemokine , extracellular matrix , fibronectin , biochemistry , enzyme
Abstract 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 CXCR 4, the receptor for the stroma‐derived factor 1 chemokine. CXCR 4 is crucial in the trafficking of hematopoietic stem cells from/to the bone marrow, which involves also uPAR . Both uPAR and CXCR 4 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 CXCR 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 uPAR and CXCR 4 in AML cell lines. Indeed, these miRs directly target the 3′untranslated region of both uPAR ‐ and CXCR 4‐ mRNA s; accordingly, uPAR / CXCR 4 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 / CXCR 4 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 .