title: A p53-dependent tumor suppressor network is induced by selective miR-125a-5p inhibition in multiple myeloma cells.
abstract: The analysis of deregulated microRNAs (miRNAs) is emerging as a novel approach to disclose the regulation of tumor suppressor or tumor promoting pathways in tumor cells. Targeting aberrantly expressed miRNAs is therefore a promising strategy for cancer treatment. By miRNA profiling of primary plasma cells from multiple myeloma (MM) patients, we previously reported increased miR-125a-5p levels associated to specific molecular subgroups. On these premises, we aimed at investigating the biological effects triggered by miR-125a-5p modulation in MM cells. Expression of p53 pathway-related genes was down-regulated in MM cells transfected with miR-125a-5p mimics. Luciferase reporter assays confirmed specific p53 targeting at 3'UTR level by miR-125a-5p mimics. Interestingly, bone marrow stromal cells (BMSCs) affected the miR-125a-5p/p53 axis, since adhesion of MM cells to BMSCs strongly up-regulated miR-125a-5p levels, while reduced p53 expression. Moreover, ectopic miR-125a-5p reduced, while miR-125-5p inhibitors promoted, the expression of tumor suppressor miR-192 and miR-194, transcriptionally regulated by p53. Lentiviral-mediated stable inhibition of miR-125a-5p expression in wild-type p53 MM cells dampened cell growth, increased apoptosis and reduced cell migration. Importantly, inhibition of in vitro MM cell proliferation and migration was also achieved by synthetic miR-125a-5p inhibitors and was potentiated by the co-expression of miR-192 or miR-194. Taken together, our data indicate that miR-125a-5p antagonism results in the activation of p53 pathway in MM cells, underlying the crucial role of this miRNA in the biopathology of MM and providing the molecular rationale for the combinatory use of miR-125a inhibitors and miR-192 or miR-194 mimics for MM treatment.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Leotta
authors.forename: Lavinia
authors.initials: L
authors.lastname: Biamonte
authors.forename: Lavinia
authors.initials: L
authors.lastname: Raimondi
authors.forename: Domenica
authors.initials: D
authors.lastname: Ronchetti
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leone
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Pitari
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53