title: DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma.
abstract: Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein-coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR-29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth-inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.forename: Marzia
authors.initials: M
authors.lastname: Leotta
authors.forename: Dina
authors.initials: D
authors.lastname: Bellizzi
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Aquila
authors.forename: Marta
authors.initials: M
authors.lastname: Lionetti
authors.forename: Fernanda
authors.initials: F
authors.lastname: Fabiani
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leone
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gullà
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
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
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D032701:Biomimetics; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle; D049109:Cell Proliferation; D060833:Cellular Microenvironment / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D007952:Leukemia, Plasma Cell / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000138:chemical synthesis / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000097584:DNA Methyltransferase 3B
chemical_list: D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D014408:Biomarkers, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C532045:MIRN29a microRNA, human