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

Oncogene volume 35, pages 3944–3954 (2016)Cite this article

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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.

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Acknowledgements

We are indebted to Cristina Ghinelli for editing the manuscript. We wish to thank Dr Gianfranco Mattia for the assessment of immunofluorescence analysis on the exosome fusion. We are also grateful to Prof. Alain Israel and Dr Johannes Schmid for sharing NF-κB reporter and plasmids. This work was supported by grants from the Italian Association for Cancer Research (AIRC project: IG2013_14049 to KS; IG2012_13247 to AC), Ministry of Education, Research and Universities (FIRB project: RBAP11884 M_005 to KS), Ministry of Health (PROVABES project: PER-2011-2353839 to PP and KS), Austrian Science Fund (project: P24708-B21 and PROVABES project: I-1225-B19 to HK). Selena Ventura is in receipt of the fellowship ‘Guglielmina Lucatello e Gino Mazzega’ granted by Fondazione Italiana per la Ricerca sul Cancro (FIRC project code: 13811).

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  1. A Carè and K Scotlandi: These two authors shared the seniorship.

Authors and Affiliations

  1. CRS Development of Biomolecular Therapies, Experimental Oncology Laboratory, Rizzoli Istituto Ortopedico, Bologna, Italy

    S Ventura, C Mancarella, M C Manara, P Picci & K Scotlandi

  2. Children’s Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria

    D N T Aryee & H Kovar

  3. Department of Pediatrics, Medical University, Vienna, Austria

    D N T Aryee & H Kovar

  4. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    F Felicetti, A De Feo & A Carè

  5. Department of Experimental Oncology and Molecular Medicine, Molecular Immunology Unit, Fondazione IRCCS 'Istituto Nazionale dei Tumori', Milan, Italy

    M P Colombo

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Ventura, S., Aryee, D., Felicetti, F. et al. CD99 regulates neural differentiation of Ewing sarcoma cells through miR-34a-Notch-mediated control of NF-κB signaling. Oncogene 35, 3944–3954 (2016). https://doi.org/10.1038/onc.2015.463

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