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.
Nucleic Acids Res. 2013 Oct;41(19):8853-71. doi: 10.1093/nar/gkt678. Epub 2013 Aug 8.
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.
尤因肉瘤是第二常见的小儿骨肿瘤。在大多数患者中，染色体易位导致 EWS-FLI1 嵌合转录因子的表达，该转录因子是该病理学中的主要癌基因。尤因肉瘤的相对遗传简单性使其特别适合以系统的方式研究癌症。沉默 EWS-FLI1 诱导细胞周期改变，并最终导致细胞凋亡，但这种表型的确切分子机制尚不清楚。在这项研究中，通过一种原始的网络重建方法，构建了将 EWS-FLI1 与细胞周期和凋亡表型联系起来的网络。通过一种基于拟合表达谱动力学曲线的原始评分方法，使用 EWS-FLI1 沉默后的转录组时间序列来鉴定核心调节基因。然后，使用文献数据挖掘将这些调节基因连接成网络。通过在另外四个尤因细胞系上进行 siRNA/RT-QPCR 实验，评估了该网络的一个子部分的有效性，并证实了大多数连接。基于网络和转录组数据，鉴定 CUL1 为 EWS-FLI1 的一个新的潜在靶标。总之，我们使用数据集成的原始方法，提供了 EWS-FLI1 调节细胞周期和凋亡的网络模型的第一个版本。
