Let-7 Family microRNAs Regulate the Expression of the Urokinase-Receptor in Acute Myeloid Leukemia Cells

The urokinase-receptor (uPAR) exerts multiple functions supporting most cancer hallmarks. Increased uPAR expression is associated with an unfavorable prognosis in several cancer types, including hematologic malignancies. We previously reported that three oncosuppressor microRNAs (miRNAs) can target the 3'untranslated region (3'UTR) of the uPAR mRNA and that uPAR mRNA is a competitive endogenous RNA (ceRNA) able to recruit oncosuppressor miRs, thus impairing their activity. We now show that uPAR mRNA can also be targeted by oncosuppressor members of the let-7 miRNA family in acute myeloid leukemia (AML) cell lines. Indeed, let-7a, let7d and let-7g directly target the 3'UTR of uPAR mRNA, thus down-regulating uPAR expression. These let-7 miRNAs are expressed in KG1 and U937 AML cells; their levels are high in KG1 cells, which express low uPAR levels, and low in the U937 cell line, expressing high levels of uPAR. Overexpression of these miRNAs down-regulates uPAR expression and impairs the adhesion to fibronectin and migration of U937 cells, without affecting their proliferation. Accordingly, the overexpression of specific inhibitors targeting these let-7 miRNAs efficiently increases uPAR expression in KG1 cells. These results indicate that selected let-7 miRNAs regulate uPAR expression and impair the adhesion and migration of AML cells.