A novel oncogenic role for urokinase receptor in leukemia cells: molecular sponge for oncosuppressor microRNAs

Abstract

Urokinase receptor (uPAR) expression is up-regulated and represents a negative prognostic marker in most cancers. We previously reported that uPAR and CXCR4 can be regulated by common microRNAs in leukemia cells. Transcripts containing response elements for shared microRNAs in their 3’UTR may regulate their availability.We investigated uPAR 3’UTR capability to recruit microRNAs, thus regulating the expression of their targets. uPAR 3’UTR transfection in KG1 leukemia cells up-regulates the expression of endogenous uPAR. Transfection of uPAR 3’UTR, inserted downstream a reporter gene, increases uPAR expression and simultaneously down-regulates the reporter gene expression. Transfection of uPAR 3’UTR also increases CXCR4 expression; accordingly, uPAR silencing induces down-regulation of CXCR4 expression, through a mechanism involving Dicer, the endoribonuclease required for microRNA maturation.Transfection of uPAR 3’UTR also increases the expression of pro-tumoral factors and modulates cell adhesion and migration, consistently with the capability of uPAR3’UTR-recruited microRNAs to target several and different transcripts and, thus, functions.Finally, we found 3’UTR-containing variants of uPAR transcript in U937 leukemia cells, which show higher levels of uPAR expression as compared to KG1 cells, in which these variants are not detected.These results suggest that uPAR mRNA may recruit oncosuppressor microRNAs, allowing the expression of their targets.

uPAR Knockout Results in a Deep Glycolytic and OXPHOS Reprogramming in Melanoma and Colon Carcinoma Cell Lines

“…Indeed, using a siRNA, we triggered an acute effect [25], downregulating uPAR expression for a maximum of 72 h while by exploiting the CRISPR/Cas9, we obtained stable KO cell lines, forcing the cells to adapt to uPAR deprivation. Moreover, we do believe that by losing uPAR mRNA expression, all the miRNAs that are attached to its 3 UTR, as reported by Li Santi et al [30], might modulate several important biological functions. Moreover, even though the receptor pattern related to metabolism is not completely coherent among the three cell lines, we need to point out that the most similar expression levels among A375 and HCT116 clones may be due to their nature as primitive tumor-derived cells, while M6 is a cell line obtained by a metastasis in the lungs.…”

The Inhibitory Effects of Recombinant Hespintor Combined with Sorafenib on Transplanted Human Hepatoma in Nude Mice, and Transcriptional Regulation of Hespintor Based on RNA-Seq

“…It has been previously reported that 3'-UTR in uPAR and CXCR4 contains the common miRNAs response elements. In other words, up-regulated expressions of uPAR will tend to lead to up-regulated expressions of CXCR4 [23], indicating that the Hespintor could inhibit the invasion and migration of tumor cells and induce apoptosis only after reaching a certain drug concentration.…”

“…It has been previously reported that 3'-UTR in uPAR and CXCR4 contains the common miRNAs response elements. In other words, up-regulated expressions of uPAR will tend to lead to up-regulated expressions of CXCR4 23 , indicating that the Hespintor could inhibit the invasion and migration of tumor cells and induce apoptosis only after reaching a certain drug concentration. Otherwise, the insufficient concentration of Hespintor would be easy to induce ROS generation and promote the expressions of uPA by relying on the mediating role of ROS, which could explain the contradictory expressions of serpins in the tumors examined in this study to a certain extent.…”

Trdmt1 3'-untranslated region functions as a competing endogenous RNA in leukemia HL-60 cell differentiation

“…The prevalent view is that protein-coding genes must be translated into a protein to exert function. Recent studies indicated exogenous expression of the 3′UTR constructs such as uPAR, RUNX1T1, and C-Myc participate in leukemia cells migration and differentiation by regulating gene expression ( 46 ). As the most conserved member of the DNA methyltransferase family ( 7 ), Trdmt1 is found to be crucial for differentiation both in the hematopoietic system and bone marrow mesenchymal stem cells ( 8 ).…”

“…Pseudogene, lncRNA, circRNA, and mRNA can all function as ceRNAs to sponge miRNAs, consequently modulating the de-repression of miRNA targets. Compared with the non-coding RNAs, only a few mRNAs that act as ceRNAs have been mechanically and functionally characterized in the context of AML-associated aberrant gene networks (4)(5)(6).…”