Regolazione post-trascrizionale dell’espressione del recettore dell’urochinasi

Abstract

The urokinase type plasminogen activator (uPAR) is a three domain GPI-anchored cell surface receptor. uPAR expression is strongly up-regulated and represents a negative prognostic factor in various tumors, including hematologic malignancies. uPAR expression is post-transcriptionally regulated by RNA binding proteins (RBPs). RBPs bind specific sequences in the 3’untranslated region (3’UTR) of uPAR-mRNA, stabilizing or destabilizing the transcript. The 3’UTR of transcripts from a large number of genes includes target sequences also for small translational repressors RNAs (miRNAs). miRNAs play key roles in many cellular pathways; their aberrant expression is a common feature of various malignancies. We selected three miRNAs miR-146a, miR-335 and miR-622 that could bind the 3’UTR of uPAR-mRNA; these three miRNAs, as reported in literature, are expressed in CD34+ HSC or in acute myeloid leukemia (AML) cells and can act as oncosuppressors by inhibiting oncogene expression. We found that selected miRNAs regulate uPAR expression by directly targeting its 3’UTR in AML cell lines. Indeed, uPAR expression is reduced by their overexpression and increased by their specific inhibitors. Overexpression of selected miRNAs impaired cell migration, invasion and proliferation of AML cell lines. Interestingly, we found an inverse relationship between uPAR expression and miR- 146a and miR-335 levels in AML blasts. This suggests their possible role in regulating uPAR expression also in vivo. We also investigated the capability of uPAR-3’UTR to act as competing endogenous RNA (ceRNA). We showed that uPAR-3’UTR overexpression up-regulates uPAR expression and expression of other targets of selected miRNAs; these results suggest that uPAR-3’UTR may recruit selected miRNAs, allowing translation of their targets, thus acting as ceRNA. [edited by Author]