Abstract
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.
Highlights
Ewing’s sarcoma is the second most frequent pediatric bone tumor with a peak of incidence between 4 and 25 years of age
Knocking down EWS-FLI1 in Ewing sarcoma cell lines slows down proliferation and induces apoptosis in vitro [5] and in vivo [6]
The starting point of this study was the statement that EWS-FLI1 is the central and driving force of tumorigenesis in Ewing sarcoma
Summary
Ewing’s sarcoma is the second most frequent pediatric bone tumor with a peak of incidence between 4 and 25 years of age. In 85% of the patients, a causal translocation between EWS and FLI1 genes is found This leads to the expression of EWS-FLI1 chimeric transcription factor [1]. Knocking down EWS-FLI1 in Ewing sarcoma cell lines slows down proliferation and induces apoptosis in vitro [5] and in vivo [6]. Rescuing these two last phenotypes by re-expressing any other gene than EWS-FLI1 could not be accomplished so far. The impact of EWS-FLI1 on apoptosis can be explained, for instance, by its direct effect on CASP3 [16] or indirectly through regulating members of TNF- [17], IGF- [13,14] and TGFbeta signaling [12]
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