EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells
| Autor: | Claudio De Vito, Paolo Provero, Domizio Suva, Karine Baumer, Mario-Luca Suvà, Stéphane Tercier, Luisa Cironi, Ivan Stamenkovic, Jean-Marc Joseph, Tanja Petricevic, Jean-Christophe Stehle, Michalina Janiszewska, Louis Guillou, Nicolo Riggi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
cancer stem cells
Cellular differentiation SOX2 SOXB1 Transcription Factors/ metabolism Nuclear Reprogramming Tumor Cells Cultured Child Octamer Transcription Factor-3/metabolism ddc:617 miRNA145 Cell Differentiation Nanog Homeobox Protein Cellular Reprogramming Neoplastic Stem Cells/cytology/metabolism Gene Expression Regulation Neoplastic Phenotype Neoplastic Stem Cells Sarcoma Ewing's/physiopathology Stem cell Reprogramming Research Paper Homeobox protein NANOG Adult Proto-Oncogene Protein c-fli-1/ metabolism Mesenchymal Stem Cells/ cytology Adolescent Sarcoma Ewing Biology MicroRNAs/ metabolism Cancer stem cell Cell Line Tumor Genetics Homeodomain Proteins/metabolism RNA-Binding Protein EWS/ metabolism Humans Homeodomain Proteins Proto-Oncogene Protein c-fli-1 SOXB1 Transcription Factors Mesenchymal stem cell fungi Ewing sarcoma mesenchymal stem cells reprogramming Mesenchymal Stromal Cells/cytology MicroRNAs/metabolism Neoplastic Stem Cells/cytology Neoplastic Stem Cells/metabolism Proto-Oncogene Protein c-fli-1/metabolism RNA-Binding Protein EWS/metabolism SOXB1 Transcription Factors/metabolism Sarcoma Ewing/physiopathology Mesenchymal Stem Cells Embryonic stem cell MicroRNAs Cancer research RNA-Binding Protein EWS Octamer Transcription Factor-3 Developmental Biology |
| Zdroj: | Genes and Development, Vol. 24, No 9 (2010) pp. 916-932 Genes & development, vol. 24, no. 9, pp. 916-932 |
| ISSN: | 0890-9369 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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