Systems biology of Ewing sarcoma: a network model of EWS-FLI1 effect on proliferation and apoptosis.
Ewing sarcoma is the second most frequent pediatric bone tumor. In most of the patients, a chromosomal translocation leads to the expression of the EWS-FLI1 chimeric transcription factor that is the major oncogene in this pathology. Relative genetic simplicity of Ewing sarcoma makes it particularly attractive for studying cancer in a systemic manner. Silencing EWS-FLI1 induces cell cycle alteration and ultimately leads to apoptosis, but the exact molecular mechanisms underlying this phenotype are unclear. In this study, a network linking EWS-FLI1 to cell cycle and apoptosis phenotypes was constructed through an original method of network reconstruction. Transcriptome time-series after EWS-FLI1 silencing were used to identify core modulated genes by an original scoring method based on fitting expression profile dynamics curves. Literature data mining was then used to connect these modulated genes into a network. The validity of a subpart of this network was assessed by siRNA/RT-QPCR experiments on four additional Ewing cell lines and confirmed most of the links. Based on the network and the transcriptome data, CUL1 was identified as a new potential target of EWS-FLI1. Altogether, using an original methodology of data integration, we provide the first version of EWS-FLI1 network model of cell cycle and apoptosis regulation.
Institut Curie, 26 rue d'Ulm, 75248 Paris cedex 05, France, INSERM U900, Bioinformatique, biostatistique et épidémiologie d'un système complexe, Paris, France, Mines ParisTech, Fontainebleau, France, INSERM U830, Unité de Génétique et Biologie des Cancers, Paris, France and Institut Curie, Unité de génétique somatique, Paris, France.
Gautier
G
Stoll
Didier
D
Surdez
Franck
F
Tirode
Karine
K
Laud
Emmanuel
E
Barillot
Andrei
A
Zinovyev
Olivier
O
Delattre
D017209:Apoptosis / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D057225:Data Mining; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051789:Proto-Oncogene Protein c-fli-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D049490:Systems Biology; D059467:Transcriptome
C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS