title: In vitro and in vivo anti-tumor activity of miR-221/222 inhibitors in multiple myeloma.
abstract: 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.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Martino
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gullà
authors.forename: Maria Eugenia Gallo
authors.initials: ME
authors.lastname: Cantafio
authors.forename: Marta
authors.initials: M
authors.lastname: Lionetti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leone
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.forename: Pietro Hiram
authors.initials: PH
authors.lastname: Guzzi
authors.forename: Umberto
authors.initials: U
authors.lastname: Foresta
authors.forename: Francesco
authors.initials: F
authors.lastname: Conforti
authors.forename: Mario
authors.initials: M
authors.lastname: Cannataro
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; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; C525709:MIR221, human; C525710:MIR222, human