title: CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB signaling.
abstract: Sarcomas are mesenchymal tumors characterized by blocked differentiation process. In Ewing sarcoma (EWS) both CD99 and EWS-FLI1 concur to oncogenesis and inhibition of differentiation. Here, we demonstrate that uncoupling CD99 from EWS-FLI1 by silencing the former, nuclear factor-κB (NF-κB) signaling is inhibited and the neural differentiation program is re-established. NF-κB inhibition passes through miR-34a-mediated repression of Notch pathway. CD99 counteracts EWS-FLI1 in controlling NF-κB signaling through the miR-34a, which is increased and secreted into exosomes released by CD99-silenced EWS cells. Delivery of exosomes from CD99-silenced cells was sufficient to induce neural differentiation in recipient EWS cells through miR-34a inhibition of Notch-NF-κB signaling. Notably, even the partial delivery of CD99 small interfering RNA may have a broad effect on the entire tumor cell population owing to the spread operated by their miR-34a-enriched exosomes, a feature opening to a new therapeutic option.
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ventura
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University, Vienna, Austria.
authors.forename: D N T
authors.initials: DN
authors.lastname: Aryee
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Felicetti
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Feo
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Mancarella
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Manara
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Picci
authors.affiliation: Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS 'Istituto Nazionale dei Tumori', Milan, Italy.
authors.forename: M P
authors.initials: MP
authors.lastname: Colombo
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University, Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Kovar
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Carè
authors.affiliation: CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Scotlandi
mesh_terms: D000071443:12E7 Antigen / Q000502:physiology*; D002454:Cell Differentiation; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D012512:Sarcoma, Ewing / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000071443:12E7 Antigen; C061828:CD99 protein, human; C106031:EWS-FLI fusion protein; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; D051880:Receptors, Notch