Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells
Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells
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DOI：
10.1158/0008-5472.can-06-0927
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Notario, Vicente
中科院分区：
文献类型：
--
作者：
Tirado, Oscar M.;Mateo-Lozano, Silvia;Notario, Vicente
尤文氏肉瘤家族（ESFT）的肿瘤，如尤文氏肉瘤（EWS）和原始神经外胚层肿瘤（PNET），是高度侵袭性的恶性肿瘤，主要影响儿童和年轻人。ESFT表达由融合EWS基因与几个ETS基因（最常见的是FLI-1）的杂交基因编码的嵌合转录因子。EWS/FLI-1蛋白与ESFT的恶性表型有关，但其转录靶点很少。使用反义和短发夹RNA介导的基因表达敲低，阵列分析，染色质免疫沉淀方法，和再表达的研究，我们表明，窖蛋白-1（CAV 1）是一个新的EWS/FLI-1的直接目标，在ESFT细胞系和肿瘤标本中过表达，是ESFT肿瘤发生所必需的。CAV 1基因敲减导致Snail表达上调，同时E-cadherin表达减少。因此，CAV 1表达的缺失抑制了EWS细胞的非贴壁依赖性生长，并显著降低了EWS细胞源性肿瘤在裸鼠异种移植瘤中的生长，表明CAV 1促进了EWS癌变的恶性表型。在CAV 1敲除的EWS细胞中CAV 1或E-cadherin的再表达挽救了原始EWS细胞的致癌表型，表明CAV 1/Snail/E-cadherin途径在EWS/ FLI-1的致癌转化功能的表达中起着核心作用。总的来说，这些数据确定CAV 1是ESFT致瘤性的关键决定因素，并暗示靶向CAV 1可能允许为ESFT患者开发新的分子治疗策略。
Tumors of the Ewing's sarcoma family (ESFT), such as Ewing's sarcoma (EWS) and primitive neuroectodermal tumors (PNET), are highly aggressive malignancies predominantly affecting children and young adults. ESFT express chimeric transcription factors encoded by hybrid genes fusing the EWS gene with several ETS genes, most commonly FLI-1. EWS/FLI-1 proteins are responsible for the malignant phenotype of ESFT, but only few of their transcriptional targets are known. Using antisense and short hairpin RNA-mediated gene expression knockdown, array analyses, chromatin immunoprecipitation methods, and reexpression studies, we show that caveolin-1 (CAV1) is a new direct target of EWS/FLI-1 that is overexpressed in ESFT cell lines and tumor specimens and is necessary for ESFT tumorigenesis. CAV1 knockdown led to up-regulation of Snail and the concomitant loss of E-cadherin expression. Consistently, loss of CAV1 expression inhibited the anchorage-independent growth of EWS cells and markedly reduced the growth of EWS cell-derived tumors in nude mice xenografts, indicating that CAV1 promotes the malignant phenotype in EWS carcinogenesis. Reexpression of CAV1 or E-cadherin in CAV1 knockdown EWS cells rescued the oncogenic phenotype of the original EWS cells, showing that the CAV1/Snail/E-cadherin pathway plays a central role in the expression of the oncogenic transformation functions of EWS/ FLI-1. Overall, these data identify CAV1 as a key determinant of the tumorigenicity of ESFT and imply that targeting CAV1 may allow the development of new molecular therapeutic strategies for ESFT patients.