CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB signaling

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) signalin...

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Bibliographic Details
Published in:Oncogene 2016-07, Vol.35 (30), p.3944-3954
Main Authors: Ventura, S, Aryee, D N T, Felicetti, F, De Feo, A, Mancarella, C, Manara, M C, Picci, P, Colombo, M P, Kovar, H, Carè, A, Scotlandi, K
Format: Article
Language:English
Subjects:
12E7 Antigen - physiology
CD99 antigen
Cell Differentiation
Cellular proteins
Cellular signal transduction
Development and progression
Ewing's sarcoma
Ewings sarcoma
Exosomes
Genetic aspects
Health aspects
Humans
Mesenchyme
MicroRNAs - physiology
NF-kappa B - physiology
NF-κB protein
Oncogene Proteins, Fusion - physiology
Proto-Oncogene Protein c-fli-1 - physiology
Receptors, Notch - physiology
RNA, Small Interfering - genetics
RNA-Binding Protein EWS - physiology
Sarcoma, Ewing - pathology
Signal Transduction - physiology
siRNA
Tumorigenesis
Tumors
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.463