EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma
EWS-FLI1-mediated suppression of the RAS-antagonist Sprouty 1 (SPRY1) confers aggressiveness to Ewing sarcoma
复制标题
DOI：
10.1038/onc.2016.244
复制
发表时间：
2017-02-09
期刊：
影响因子：
8
通讯作者：
Alonso, J.
中科院分区：
文献类型：
--
作者：
Cidre-Aranaz, F.;Gruenewald, T. G. P.;Alonso, J.
尤文肉瘤的特征是染色体易位，将 EWS 基因与 ETS 转录因子家族的各个成员（最常见的是 FLI1）融合。 EWS-FLI1 是一种异常转录因子，通过转录诱导或抑制特定靶基因来驱动尤文肉瘤肿瘤发生。在此，我们发现 Sprouty 1 (SPRY1) 是成纤维细胞生长因子 (FGF) 受体 (FGFR) 和其他 RAS 激活受体下游的生理负反馈抑制剂，是 EWS-FLI1 抑制基因。 EWS-FLI1 敲低特别增加了 SPRY1 的表达，而其他 Sprouty 家族成员则不受影响。对一组尤文肉瘤细胞中 SPRY1 表达的分析表明，SPRY1 在尤文肉瘤细胞系中不表达，表明它可以在这些细胞中充当肿瘤抑制基因。一致认为，在三种不同的尤文肉瘤细胞系中诱导 SPRY1 会功能性损害增殖、克隆生长和迁移。此外，SPRY1 表达抑制血清和碱性 FGF (bFGF) 诱导的细胞外信号相关激酶/丝裂原激活蛋白激酶 (MAPK) 信号传导。此外，用强效 FGFR 抑制剂 PD-173074 处理尤文肉瘤细胞，可以剂量依赖性方式减少 bFGF 诱导的增殖、集落形成和体内肿瘤生长，从而模拟尤文肉瘤细胞中的 SPRY1 活性。尽管与其他肿瘤相比，SPRY1 的表达较低，但 SPRY1 在原发性尤文肉瘤肿瘤中表达不同，并且较高的表达水平与大型患者队列中预后的改善显着相关。综上所述，我们的数据表明 EWS-FLI1 介导的 SPRY1 抑制导致不受限制的 bFGF 诱导的细胞增殖，这表明靶向 FGFR/MAPK 途径可以为这种破坏性疾病构成一种有前途的治疗方法。
Ewing sarcoma is characterized by chromosomal translocations fusing the EWS gene with various members of the ETS family of transcription factors, most commonly FLI1. EWS-FLI1 is an aberrant transcription factor driving Ewing sarcoma tumorigenesis by either transcriptionally inducing or repressing specific target genes. Herein, we showed that Sprouty 1 (SPRY1), which is a physiological negative feedback inhibitor downstream of fibroblast growth factor (FGF) receptors (FGFRs) and other RAS-activating receptors, is an EWS-FLI1 repressed gene. EWS-FLI1 knockdown specifically increased the expression of SPRY1, while other Sprouty family members remained unaffected. Analysis of SPRY1 expression in a panel of Ewing sarcoma cells showed that SPRY1 was not expressed in Ewing sarcoma cell lines, suggesting that it could act as a tumor suppressor gene in these cells. In agreement, induction of SPRY1 in three different Ewing sarcoma cell lines functionally impaired proliferation, clonogenic growth and migration. In addition, SPRY1 expression inhibited extracellular signal-related kinase/mitogen-activated protein kinase (MAPK) signaling induced by serum and basic FGF (bFGF). Moreover, treatment of Ewing sarcoma cells with the potent FGFR inhibitor PD-173074 reduced bFGF-induced proliferation, colony formation and in vivo tumor growth in a dose-dependent manner, thus mimicking SPRY1 activity in Ewing sarcoma cells. Although the expression of SPRY1 was low when compared with other tumors, SPRY1 was variably expressed in primary Ewing sarcoma tumors and higher expression levels were significantly associated with improved outcome in a large patient cohort. Taken together, our data indicate that EWS-FLI1-mediated repression of SPRY1 leads to unrestrained bFGF-induced cell proliferation, suggesting that targeting the FGFR/MAPK pathway can constitute a promising therapeutic approach for this devastating disease.