CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-?B 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-?B (NF-?B) signaling is inhibited and the neural differentiation program is re-established. NF-?B inhibition passes through miR-34a-mediated repression of Notch pathway. CD99 counteracts EWS-FLI1 in controlling NF-?B 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-?B 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.

SUBMITTER: Ventura S 

PROVIDER: S-EPMC4967355 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature