title: Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence.
abstract: OBJECTIVE
  Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a.
  
  
  METHODS
  Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo.
  
  
  RESULTS
  Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity.
  
  
  CONCLUSIONS
  Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T Campanella Cancer Center, Salvatore Venuta University Campus; Pathology Unit, Magna Graecia University, Catanzaro, Italy.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Di Martino
authors.forename: Emanuela
authors.initials: E
authors.lastname: Leone
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.forename: Umberto
authors.initials: U
authors.lastname: Foresta
authors.forename: Marta
authors.initials: M
authors.lastname: Lionetti
authors.forename: Maria R
authors.initials: MR
authors.lastname: Pitari
authors.forename: Maria E Gallo
authors.initials: ME
authors.lastname: Cantafio
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gullà
authors.forename: Francesco
authors.initials: F
authors.lastname: Conforti
authors.forename: Eugenio
authors.initials: E
authors.lastname: Morelli
authors.forename: Vera
authors.initials: V
authors.lastname: Tomaino
authors.forename: Marco
authors.initials: M
authors.lastname: Rossi
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Masood A
authors.initials: MA
authors.lastname: Shammas
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D034622:RNA Interference; D014161:Transduction, Genetic; D014162:Transfection; D047368:Tumor Burden; D059016:Tumor Microenvironment
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs