EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.

Détails

Ressource 1Télécharger: PMID20382729.pdf (1504.54 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_737C56E6F022
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.
Périodique
Genes & development
Auteur(s)
Riggi N., Suvà M.L., De Vito C., Provero P., Stehle J.C., Baumer K., Cironi L., Janiszewska M., Petricevic T., Suvà D., Tercier S., Joseph J.M., Guillou L., Stamenkovic I.
ISSN
1549-5477 (Electronic)
ISSN-L
0890-9369
Statut éditorial
Publié
Date de publication
05/2010
Peer-reviewed
Oui
Volume
24
Numéro
9
Pages
916-932
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.
Mots-clé
Adolescent, Adult, Cell Differentiation, Cell Line, Tumor, Cellular Reprogramming, Child, Gene Expression Regulation, Neoplastic, Homeodomain Proteins/metabolism, Humans, Mesenchymal Stromal Cells/cytology, MicroRNAs/metabolism, Nanog Homeobox Protein, Neoplastic Stem Cells/cytology, Neoplastic Stem Cells/metabolism, Octamer Transcription Factor-3/metabolism, Phenotype, Proto-Oncogene Protein c-fli-1/metabolism, RNA-Binding Protein EWS/metabolism, SOXB1 Transcription Factors/metabolism, Sarcoma, Ewing/physiopathology, Tumor Cells, Cultured
Pubmed
Web of science
Open Access
Oui
Création de la notice
18/05/2010 15:48
Dernière modification de la notice
08/05/2019 20:25
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