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Molecular and Cellular Biology, August 2004, p. 7275-7283, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7275-7283.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

EWS/FLI-1 Silencing and Gene Profiling of Ewing Cells Reveal Downstream Oncogenic Pathways and a Crucial Role for Repression of Insulin-Like Growth Factor Binding Protein 3{dagger}

Alexandre Prieur,1,{ddagger} Franck Tirode,1,{ddagger} Pinchas Cohen,2 and Olivier Delattre1*

Laboratoire de Pathologie Moléculaire des Cancers, INSERM U509, Section de Recherche, Institut Curie, 75248 Paris, France,1 Department of Pediatrics, University of California, Los Angeles, Los Angeles, California 90095-17522

Received 17 March 2004/ Returned for modification 3 April 2004/ Accepted 20 May 2004

Ewing tumors are characterized by abnormal transcription factors resulting from the oncogenic fusion of EWS with members of the ETS family, most commonly FLI-1. RNA interference targeted to the junction between EWS and FLI-1 sequences was used to inactivate the EWS/FLI-1 fusion gene in Ewing cells and to explore the resulting phenotype and alteration of the gene expression profile. Loss of expression of EWS/FLI-1 resulted in the complete arrest of growth and was associated with a dramatic increase in the number of apoptotic cells. Gene profiling of Ewing cells in which the EWS/FLI-1 fusion gene had been inactivated identified downstream targets which could be grouped in two major functional clusters related to extracellular matrix structure or remodeling and regulation of signal transduction pathways. Among these targets, the insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of insulin-like growth factor 1 (IGF-1) proliferation and survival signaling, was strongly induced upon treating Ewing cells with EWS/FLI-1-specific small interfering RNAs. We show that EWS/FLI-1 can bind the IGFBP-3 promoter in vitro and in vivo and can repress its activity. Moreover, IGFBP-3 silencing can partially rescue the apoptotic phenotype caused by EWS/FLI-1 inactivation. Finally, IGFBP-3-induced Ewing cell apoptosis relies on both IGF-1-dependent and -independent pathways. These findings therefore identify the repression of IGFBP-3 as a key event in the development of Ewing's sarcoma.

* Corresponding author. Mailing address: Laboratoire de Pathologie Moléculaire des Cancers, INSERM U509, Section de Recherche, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France. Phone: 33 1 42 34 66 81. Fax: 33 1 42 34 66 30. E-mail: olivier.delattre{at}curie.fr.

{dagger} This work is dedicated to our colleague Thomas Melot.

{ddagger} A.P. and F.T. contributed equally to this work.

Molecular and Cellular Biology, August 2004, p. 7275-7283, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7275-7283.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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