In Vitro and in Vivo Anti-tumor Activity of miR-221/222 Inhibitors in Multiple Myeloma
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Maria Teresa Di Martino1,2, Annamaria Gullà1, Maria Eugenia Gallo Cantafio1, Marta Lionetti3, Emanuela Leone1, Nicola Amodio1, Pietro Hiram Guzzi4, Umberto Foresta1, Francesco Conforti2, Mario Cannataro4, Antonino Neri3, Antonio Giordano5,6, Pierosandro Tagliaferri1,2, and Pierfrancesco Tassone1,2,6
1 Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
2 Medical Oncology, Tommaso Campanella Cancer Center, Catanzaro, Italy
3 Department of Medical Sciences University of Milan, Hematology1, IRCCS Policlinico Foundation, Milan, Italy;
4 Department of Medical and Surgical Sciences, Laboratory of Bioinformatics Unit;
5 Department of Human Pathology and Oncology, University of Siena, Siena, Italy;
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-221, miR-222, microRNA, miRNA, multiple myeloma, plasma cell leukemia
Received: January 15, 2013 Accepted: February 22, 2013 Published: February 24, 2013
A rising body of evidence suggests that silencing microRNAs (miRNAs) with oncogenic potential may represent a successful therapeutic strategy for human cancer. We investigated the therapeutic activity of miR-221/222 inhibitors against human multiple myeloma (MM) cells. Enforced expression of miR-221/222 inhibitors triggered in vitro anti-proliferative effects and up-regulation of canonic miR-221/222 targets, including p27Kip1, PUMA, PTEN and p57Kip2, in MM cells highly expressing miR-221/222. Conversely, transfection of miR-221/222 mimics increased S-phase and down-regulated p27Kip1 protein expression in MM with low basal miR-221/222 levels. The effects of miR-221/222 inhibitors was also evaluated in MM xenografts in SCID/NOD mice. Significant anti-tumor activity was achieved in xenografted mice by the treatment with miR-221/222 inhibitors, together with up-regulation of canonic protein targets in tumors retrieved from animals. These findings provide proof of principle that silencing the miR-221/222 cluster exerts significant therapeutic activity in MM cells with high miR-221/222 level of expression, which mostly occurs in TC2 and TC4 MM groups. These findings suggest that MM genotyping may predict the therapeutic response. All together our results support a framework for clinical development of miR-221/222 inhibitors-based therapeutic strategy in this still incurable disease.
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