IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells
Copyright policy )IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells
The EWS-FLI-1 fusion protein is associated with 85-90% of Ewing's sarcoma family tumors (ESFT), the remaining 10-15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin.To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS-ERG expression and none could express FUS-ERG for more than 3-5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression.Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis.
- University of Turin Italy
- University of Lausanne Switzerland
- University Hospital of Lausanne Switzerland
- University Hospital of Geneva Switzerland
- University of Geneva Switzerland
Oncogene Proteins, Fusion, Animals; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin-Like Growth Factor I/metabolism; Mesenchymal Stromal Cells/cytology; Mesenchymal Stromal Cells/metabolism; Mice; Mice, Inbred C57BL; Models, Biological; Oncogene Proteins, Fusion/chemistry; Oncogene Proteins, Fusion/metabolism; Phenotype; Promoter Regions, Genetic; Proto-Oncogene Protein c-fli-1/chemistry; Proto-Oncogene Protein c-fli-1/metabolism; RNA-Binding Protein EWS; RNA-Binding Protein FUS/metabolism; Transcription Factors/metabolism, Proto-Oncogene Protein c-fli-1, Science, Gene Expression Profiling, Q, R, Mesenchymal Stem Cells, Models, Biological, Mice, Inbred C57BL, Mice, Phenotype, Gene Expression Regulation, Medicine, Animals, Humans, RNA-Binding Protein FUS, Insulin-Like Growth Factor I, RNA-Binding Protein EWS, Promoter Regions, Genetic, Ewing sarcoma, Research Article, Transcription Factors
Oncogene Proteins, Fusion, Animals; Gene Expression Profiling; Gene Expression Regulation; Humans; Insulin-Like Growth Factor I/metabolism; Mesenchymal Stromal Cells/cytology; Mesenchymal Stromal Cells/metabolism; Mice; Mice, Inbred C57BL; Models, Biological; Oncogene Proteins, Fusion/chemistry; Oncogene Proteins, Fusion/metabolism; Phenotype; Promoter Regions, Genetic; Proto-Oncogene Protein c-fli-1/chemistry; Proto-Oncogene Protein c-fli-1/metabolism; RNA-Binding Protein EWS; RNA-Binding Protein FUS/metabolism; Transcription Factors/metabolism, Proto-Oncogene Protein c-fli-1, Science, Gene Expression Profiling, Q, R, Mesenchymal Stem Cells, Models, Biological, Mice, Inbred C57BL, Mice, Phenotype, Gene Expression Regulation, Medicine, Animals, Humans, RNA-Binding Protein FUS, Insulin-Like Growth Factor I, RNA-Binding Protein EWS, Promoter Regions, Genetic, Ewing sarcoma, Research Article, Transcription Factors
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