title: EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells.
abstract: 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.
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Lausanne, Lausanne CH-1011, Switzerland.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Riggi
authors.forename: Mario-Luca
authors.initials: ML
authors.lastname: Suvà
authors.forename: Claudio
authors.initials: C
authors.lastname: De Vito
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Stehle
authors.forename: Karine
authors.initials: K
authors.lastname: Baumer
authors.forename: Luisa
authors.initials: L
authors.lastname: Cironi
authors.forename: Michalina
authors.initials: M
authors.lastname: Janiszewska
authors.forename: Tanja
authors.initials: T
authors.lastname: Petricevic
authors.forename: Domizio
authors.initials: D
authors.lastname: Suvà
authors.forename: Stéphane
authors.initials: S
authors.lastname: Tercier
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Joseph
authors.forename: Louis
authors.initials: L
authors.lastname: Guillou
authors.forename: Ivan
authors.initials: I
authors.lastname: Stamenkovic
mesh_terms: 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
chemical_list: 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
references.citation: Nature. 2009 Aug 27;460(7259):1149-53
references.pmid: 19668189
references.citation: Cell Stem Cell. 2009 Apr 3;4(4):336-47
references.pmid: 19341623
references.citation: Int J Cancer. 2002 Jul 1;100(1):49-56
references.pmid: 12115586
references.citation: Cell. 2009 May 15;137(4):647-58
references.pmid: 19409607
references.citation: Nature. 1992 Sep 10;359(6391):162-5
references.pmid: 1522903
references.citation: Cancer Res. 2008 Apr 1;68(7):2176-85
references.pmid: 18381423
references.citation: Nat Genet. 2009 Nov;41(11):1238-42
references.pmid: 19801978
references.citation: Cancer Res. 2004 Nov 15;64(22):8213-21
references.pmid: 15548687
references.citation: Cancer Res. 2006 Oct 1;66(19):9339-44
references.pmid: 16990346
references.citation: Cancer Cell. 2002 May;1(4):393-401
references.pmid: 12086853
references.citation: Nat Rev Cancer. 2003 Sep;3(9):685-94
references.pmid: 12951587
references.citation: Genes Dev. 2007 Nov 15;21(22):2845-9
references.pmid: 18006680
references.citation: Cancer Lett. 2007 Aug 28;254(1):1-10
references.pmid: 17250957
references.citation: Nature. 2008 Oct 16;455(7215):930-5
references.pmid: 18724359
references.citation: Dev Neurosci. 2004 Mar-Aug;26(2-4):148-65
references.pmid: 15711057
references.citation: Cell. 2008 Feb 22;132(4):567-82
references.pmid: 18295576
references.citation: PLoS One. 2008 Jul 09;3(7):e2634
references.pmid: 18648544
references.citation: Cell. 2009 May 15;137(4):606-8
references.pmid: 19450510
references.citation: Cell Stem Cell. 2009 Apr 3;4(4):301-12
references.pmid: 19341620
references.citation: Cancer Res. 2009 Sep 15;69(18):7140-50
references.pmid: 19738075
references.citation: J Biol Chem. 2001 Nov 9;276(45):41977-84
references.pmid: 11553628
references.citation: Oncogene. 2009 May 7;28(18):1960-70
references.pmid: 19330021
references.citation: Biostatistics. 2003 Apr;4(2):249-64
references.pmid: 12925520
references.citation: Cancer Cell. 2007 May;11(5):421-9
references.pmid: 17482132
references.citation: Cancer Res. 2003 Sep 15;63(18):5821-8
references.pmid: 14522905
references.citation: Nature. 2009 Aug 27;460(7259):1140-4
references.pmid: 19668186
references.citation: Stem Cells. 2005 Jun-Jul;23(6):738-51
references.pmid: 15917470
references.citation: Stem Cells. 2008 Aug;26(8):1931-8
references.pmid: 18388306
references.citation: Cancer Lett. 2009 Oct 8;283(2):125-34
references.pmid: 19217204
references.citation: J Pathol. 2007 Sep;213(1):4-20
references.pmid: 17691072
references.citation: Pediatr Blood Cancer. 2008 Aug;51(2):228-34
references.pmid: 18435455
references.citation: Genes Dev. 2009 Sep 15;23(18):2134-9
references.pmid: 19696146
references.citation: Cell. 2007 Jun 29;129(7):1377-88
references.pmid: 17604725
references.citation: Cancer Res. 2005 Oct 15;65(20):9226-35
references.pmid: 16230383
references.citation: Clin Cancer Res. 2007 Apr 15;13(8):2429-40
references.pmid: 17438102
references.citation: Nature. 2008 Oct 16;455(7215):967-70
references.pmid: 18923523
references.citation: Cancer Res. 2009 Mar 1;69(5):1776-81
references.pmid: 19208848
references.citation: Neuron. 2003 Aug 28;39(5):749-65
references.pmid: 12948443
references.citation: Cancer Res. 2005 Dec 15;65(24):11459-68
references.pmid: 16357154
references.citation: Hum Mol Genet. 2008 Nov 1;17(21):3411-25
references.pmid: 18689800
references.citation: Lab Invest. 2001 Jun;81(6):905-12
references.pmid: 11406651
references.citation: J Cell Physiol. 2004 Jan;198(1):110-8
references.pmid: 14584050
references.citation: J Cell Physiol. 2008 Mar;214(3):588-94
references.pmid: 17786951
references.citation: Bioinformatics. 2006 Nov 15;22(22):2825-7
references.pmid: 16982708
references.citation: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1545-64
references.pmid: 16939974
references.citation: Oncogene. 2001 Oct 11;20(46):6731-41
references.pmid: 11709708
references.citation: Cell Stem Cell. 2008 Dec 4;3(6):595-605
references.pmid: 19041776
references.citation: Nat Rev Drug Discov. 2009 Sep;8(9):709-23
references.pmid: 19629074
references.citation: Oncogene. 2001 May 31;20(25):3258-65
references.pmid: 11423975
references.citation: FEBS Lett. 2004 Aug 27;573(1-3):83-92
references.pmid: 15327980
references.citation: Cell Stem Cell. 2007 Oct 11;1(4):389-402
references.pmid: 18371377