Cidre-Aranaz F, Grünewald T G P, Surdez D, García-García L, Carlos Lázaro J, Kirchner T, González-González L, Sastre A, García-Miguel P, López-Pérez S E, Monzón S, Delattre O, Alonso J
Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Majadahonda, Spain.
INSERM U830 'Genetics and Biology of Cancers' Institut Curie Research Center, Paris, France.
Oncogene. 2017 Feb 9;36(6):766-776. doi: 10.1038/onc.2016.244. Epub 2016 Jul 4.
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.
尤因肉瘤的特征是染色体易位，使EWS基因与ETS转录因子家族的多个成员融合，其中最常见的是FLI1。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因肉瘤的肿瘤发生。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激活受体下游的一种生理性负反馈抑制剂，是一个受EWS-FLI1抑制的基因。特异性敲低EWS-FLI1可增加SPRY1的表达，而其他Sprouty家族成员不受影响。对一组尤因肉瘤细胞中SPRY1表达的分析表明，SPRY1在尤因肉瘤细胞系中不表达，这表明它可能在这些细胞中作为一种肿瘤抑制基因发挥作用。与此一致的是，在三种不同的尤因肉瘤细胞系中诱导SPRY1表达会在功能上损害细胞增殖、克隆形成和迁移。此外，SPRY1表达抑制了血清和碱性FGF（bFGF）诱导的细胞外信号调节激酶/丝裂原活化蛋白激酶（MAPK）信号传导。此外，用强效FGFR抑制剂PD-173074处理尤因肉瘤细胞可剂量依赖性地降低bFGF诱导的细胞增殖、集落形成和体内肿瘤生长，从而模拟了SPRY1在尤因肉瘤细胞中的活性。尽管与其他肿瘤相比，SPRY1的表达较低，但在原发性尤因肉瘤肿瘤中其表达存在差异，在一个大型患者队列中，较高的表达水平与较好的预后显著相关。综上所述，我们的数据表明EWS-FLI1介导的对SPRY1的抑制导致bFGF诱导的细胞增殖不受抑制，这表明靶向FGFR/MAPK途径可能是治疗这种毁灭性疾病的一种有前景的治疗方法。
