EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.
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.
Riggi
Nicolò
N
Division of Experimental Pathology, Institute of Pathology, University of Lausanne, Lausanne CH-1011, Switzerland.
Suvà
Mario-Luca
ML
De Vito
Claudio
C
Provero
Paolo
P
Stehle
Jean-Christophe
JC
Baumer
Karine
K
Cironi
Luisa
L
Janiszewska
Michalina
M
Petricevic
Tanja
T
Suvà
Domizio
D
Tercier
Stéphane
S
Joseph
Jean-Marc
JM
Guillou
Louis
L
Stamenkovic
Ivan
I
D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D002648:Child; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D035683:MicroRNAs / Q000378:metabolism*; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D010641:Phenotype; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000503:physiopathology; D014407:Tumor Cells, Cultured
C078433:FLI1 protein, human; D018398:Homeodomain Proteins; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
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