Faculty of Biology and Medicine, Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
PLoS One. 2011;6(8):e23592. doi: 10.1371/journal.pone.0023592. Epub 2011 Aug 10.
Ewing's sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA) expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC) and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17-92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.
尤因氏肉瘤家族肿瘤（ESFT）是儿童和青少年中第二常见的骨恶性肿瘤，其特征是独特的染色体易位，在 85%的病例中导致 EWS-FLI-1 融合蛋白的表达。EWS-FLI-1 作为一种异常转录因子，既能诱导又能抑制其靶基因库中的成员。我们最近证明，EWS-FLI-1 可以改变 microRNA（miRNA）的表达，miRNA145 是 EWS-FLI-1 的直接靶标，其抑制与 ESFT 的发展有关。在这里，我们使用 miRNA 芯片比较了人类间充质干细胞（MSC）和 ESFT 细胞系的全局 miRNA 表达谱，并表明 ESFT 显示出独特的 miRNA 特征，包括致癌 miRNA17-92 簇的诱导和肿瘤抑制因子 let-7 家族的抑制。我们证明，EWS-FLI-1 对 let-7a 的直接抑制参与了 ESFT 细胞体内的致瘤潜能。let-7a 表达调节 ESFT 生长的机制表明是由其靶基因 HMGA2 介导的，因为 let-7a 的过表达和 HMGA2 的抑制都阻断了 ESFT 细胞的致瘤性。与这些观察结果一致，向携带 ESFT 的小鼠体内系统递送合成的 let-7a 恢复了肿瘤细胞中的表达，降低了 HMGA2 的表达水平，并导致 ESFT 体内生长抑制。我们的观察结果提供了证据，表明 let-7a 靶基因表达的失调参与了 ESFT 的发展，并确定 let-7a 是最具侵袭性儿科恶性肿瘤之一有前途的新治疗靶点。
