IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells
IGF1 Is a Common Target Gene of Ewing's Sarcoma Fusion Proteins in Mesenchymal Progenitor Cells
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DOI：
10.1371/journal.pone.0002634
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发表时间：
2008-07-09
期刊：
影响因子：
3.7
通讯作者：
Stamenkovic, Ivan
中科院分区：
文献类型：
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作者：
Cironi, Luisa;Riggi, Nicolo;Stamenkovic, Ivan
背景资料：EWS-FLI-1融合蛋白与85-90%的尤文氏肉瘤家族肿瘤（ESFT）相关，其余10-15%的病例表达编码EWS或FUS的嵌合基因，所述嵌合基因融合至几种ets转录因子家族成员之一，包括ERG-1、FEV、ETV 1和ETV 6。ESFT的生长和存活依赖于胰岛素样生长因子-1（IGF-1），最近的证据表明间充质祖细胞/干细胞构成了ESFT的候选来源。方法学/主要发现：为了解决ESFT相关融合蛋白之间的功能相关性，我们比较了小鼠祖细胞（MPC）对EWS-FLI-1的容许性，EWS-ERG和FUS-ERG表达，并评估相应的表达谱变化。然而，所有测试的MPC分离株都可以稳定表达EWS-FLI-1，只有一些持续稳定的EWS-ERG表达，并且没有一个可以表达FUS-ERG超过3-5天。三种融合蛋白在MPC中分别诱导和抑制的基因总数中只有14%和4%是共有的。然而，所有这三种融合蛋白，但无论是FLI-1，也不是ERG-1单独，激活IGF 1启动子和诱导IGF 1 expression.Conclusion/Significance：而不同的ESFT相关的融合蛋白的表达可能需要不同的细胞微环境，并诱导转录组的变化有限的相似性，IGF 1的诱导可能提供一个共同的机制，他们的影响在ESFT发病机制。
Background: The EWS-FLI-1 fusion protein is associated with 85-90% of Ewing's sarcoma family tumors (ESFT), the remaining 10-15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin.Methodology/Principal Findings: To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS- ERG expression and none could express FUS-ERG for more than 3-5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression.Conclusion/Significance: Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis.