Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells
Inducible expression of chimeric EWS/ETS proteins confers Ewing's family tumor-like phenotypes to human mesenchymal progenitor cells
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DOI：
10.1128/mcb.00740-07
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发表时间：
2008-04-01
影响因子：
5.3
通讯作者：
Kiyokawa, Nobutaka
中科院分区：
文献类型：
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作者：
Miyagawa, Yoshitaka;Okita, Hajime;Kiyokawa, Nobutaka
尤因氏家族肿瘤（EFT）是一种罕见的起源不明的儿科肿瘤，发生在骨和软组织中。 EFT 中发现的特定染色体易位导致 EWS 与 ets 转录因子基因 (ETS) 的子集融合，产生嵌合 EWS/ETS 蛋白。这些蛋白质被认为在 EFT 的发生和进展中发挥着至关重要的作用。然而，EWS/ETS 介导的发病机制仍不清楚。在这里，我们报告了在人骨髓源性间充质祖细胞（MPC）中建立了四环素控制的 EWS/ETS 诱导系统。 EWS/FLI1 和 EWS/ERG 蛋白的异位表达导致形态发生巨大变化，即从间充质纺锤形细胞变为小圆形至多边形细胞，这是 EFT 的特征之一。 EWS/ETS 还诱导 MPC 的免疫表型变化，包括间充质阳性标记物 CD10 和 CD13 的消失以及 EFT 阳性标记物 CD54、CD99、CD117 和 CD271 的上调。此外，在 EWS/ETS 存在的情况下，观察到从 MPC 的基因表达谱到 EFT 的基因表达谱的显着转变。结合 EWS/ETS 增强细胞侵入基质胶的能力的观察结果，这些结果表明 EWS/ETS 蛋白有助于细胞特征的改变，并赋予人类 MPC 类似 EFT 的表型。
Ewing's family tumor (EFT) is a rare pediatric tumor of unclear origin that occurs in bone and soft tissue. Specific chromosomal translocations found in EFT cause EWS to fuse to a subset of ets transcription factor genes (ETS), generating chimeric EWS/ETS proteins. These proteins are believed to play a crucial role in the onset and progression of EFT. However, the mechanisms responsible for the EWS/ETS-mediated onset remain unclear. Here we report the establishment of a tetracycline-controlled EWS/ETS-inducible system in human bone marrow-derived mesenchymal progenitor cells (MPCs). Ectopic expression of both EWS/FLI1 and EWS/ERG proteins resulted in a dramatic change of morphology, i.e., from a mesenchymal spindle shape to a small round-to-polygonal cell, one of the characteristics of EFT. EWS/ETS also induced immunophenotypic changes in MPCs, including the disappearance of the mesenchyme-positive markers CD10 and CD13 and the up-regulation of the EFT-positive markers CD54, CD99, CD117, and CD271. Furthermore, a prominent shift from the gene expression profile of MPCs to that of EFT was observed in the presence of EWS/ETS. Together with the observation that EWS/ETS enhances the ability of cells to invade Matrigel, these results suggest that EWS/ETS proteins contribute to alterations of cellular features and confer an EFT-like phenotype to human MPCs.