title: A molecular function map of Ewing's sarcoma.
abstract: BACKGROUND
  EWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing's sarcoma family tumors (ESFT) and is thought to initiate the development of the disease. Previous genomic profiling experiments have identified EWS-FLI1-regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1-dependent molecular functions characterizing this aggressive cancer is lacking.
  
  
  RESULTS
  In this study, a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT. Out of 80 normal tissues tested, mesenchymal progenitor cells (MPC) were found to fit the hypothesis that EWS-FLI1 is the driving transcriptional force in ESFT best and were therefore used as the reference tissue for the construction of the molecular function map. The interrelations of molecular pathways were visualized by measuring the similarity among annotated gene functions by gene sharing. The molecular function map highlighted distinct clusters of activities for EWS-FLI1 regulated genes in ESFT and revealed a striking difference between EWS-FLI1 up- and down-regulated genes: EWS-FLI1 induced genes mainly belong to cell cycle regulation, proliferation, and response to DNA damage, while repressed genes were associated with differentiation and cell communication.
  
  
  CONCLUSIONS
  This study revealed that EWS-FLI1 combines by distinct molecular mechanisms two important functions of cellular transformation in one protein, growth promotion and differentiation blockage. By taking MPC as a reference tissue, a significant EWS-FLI1 signature was discovered in ESFT that only partially overlapped with previously published EWS-FLI1-dependent gene expression patterns, identifying a series of novel targets for the chimeric protein in ESFT. Our results may guide target selection for future ESFT specific therapies.
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kauer
authors.forename: Jozef
authors.initials: J
authors.lastname: Ban
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kofler
authors.forename: Bob
authors.initials: B
authors.lastname: Walker
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.forename: Paul
authors.initials: P
authors.lastname: Meltzer
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D059630:Mesenchymal Stem Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000502:physiology*; D034802:RNA-Binding Protein EWS; D012512:Sarcoma, Ewing / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS