DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma
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Nicola Amodio1, Marzia Leotta1, Dina Bellizzi2, Maria Teresa Di Martino1, Patrizia D’Aquila2, Marta Lionetti3, Fernanda Fabiani1, Emanuela Leone1, Anna Maria Gullà1, Giuseppe Passarino2, Michele Caraglia4, Massimo Negrini5, Antonino Neri3, Antonio Giordano6, Pierosandro Tagliaferri1 and Pierfrancesco Tassone1,6
1 Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy
2 Department of Cell Biology, University of Calabria, Cosenza
3 Department of Medical Sciences University of Milan, Hematology 1, IRCCS Policlinico Foundation, Milan, Italy
4 Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy
5 Department of Experimental Medicine and Diagnostics,University of Ferrara
6 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
Pierfrancesco Tassone, email:
Keywords: miR-29b, microRNA, multiple myeloma, DNA methyltransferases, DNMT
Received: September 21, 2012, Accepted: October 19, 2012, Published: October 21, 2012
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.
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