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Updated: Mar 29, 2026
Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells
Published on: April 7, 2017
CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB
S Ventura1, D N T Aryee2,3, F Felicetti4
1CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy.
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.
Insights
Silencing CD99 in Ewing sarcoma (EWS) inhibits NF-κB signaling and restores neural differentiation via exosomal miR-34a, suggesting a novel therapeutic strategy for this mesenchymal tumor.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Sarcomas are mesenchymal tumors with blocked differentiation.
- In Ewing sarcoma (EWS), CD99 and EWS-FLI1 drive oncogenesis and inhibit differentiation.
- Targeting these pathways is crucial for EWS treatment.
Purpose of the Study:
- To investigate the role of CD99 in EWS oncogenesis and differentiation.
- To explore the mechanism by which CD99 influences NF-κB signaling and neural differentiation.
- To evaluate the therapeutic potential of targeting CD99-EWS-FLI1 interaction.
Main Methods:
- CD99 silencing in EWS cells.
- Analysis of NF-κB signaling pathway activation.
- Investigation of microRNA (miR-34a) expression and secretion.
- Exosome isolation and characterization.
- Assessment of neural differentiation markers.
- Inhibition of Notch pathway signaling.
Main Results:
- CD99 silencing abrogated EWS-FLI1-driven oncogenesis and re-established neural differentiation.
- NF-κB signaling inhibition was mediated by miR-34a, which repressed the Notch pathway.
- CD99-silenced EWS cells secreted miR-34a-enriched exosomes that induced differentiation in recipient cells.
Conclusions:
- CD99 plays a critical role in EWS oncogenesis by maintaining NF-κB signaling.
- Exosomal transfer of miR-34a from CD99-silenced cells offers a novel mechanism for intercellular communication and therapeutic intervention.
- Targeting CD99 and leveraging exosome-mediated delivery presents a promising therapeutic strategy for Ewing sarcoma.
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