title: Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing's sarcoma.
abstract: Our understanding of Ewing's sarcoma development mediated by the EWS/FLI fusion protein has been limited by a lack of knowledge regarding the tumor cell of origin. To circumvent this, we analyzed the function of EWS/FLI in Ewing's sarcoma itself. By combining retroviral-mediated RNA interference with reexpression studies, we show that ongoing EWS/FLI expression is required for the tumorigenic phenotype of Ewing's sarcoma. We used this system to define the full complement of EWS/FLI-regulated genes in Ewing's sarcoma. Functional analysis revealed that NKX2.2 is an EWS/FLI-regulated gene that is necessary for oncogenic transformation in this tumor. Thus, we developed a highly validated transcriptional profile for the EWS/FLI fusion protein and identified a critical target gene in Ewing's sarcoma development.
authors.affiliation: The Center for Children, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Smith
authors.forename: Leah A
authors.initials: LA
authors.lastname: Owen
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Trem
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Wong
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Whangbo
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lessnick
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051789:Proto-Oncogene Protein c-fli-1; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034802:RNA-Binding Protein EWS; D012190:Retroviridae / Q000235:genetics; D012512:Sarcoma, Ewing / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D029961:Zebrafish Proteins
chemical_list: C106031:EWS-FLI fusion protein; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish