EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1.
EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1.
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DOI：
10.18632/genesandcancer.159
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发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
Shiio, Yuzuru
中科院分区：
文献类型：
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作者：
Jayabal, Panneerselvam;Houghton, Peter J;Shiio, Yuzuru
尤文肉瘤是一种侵袭性儿童骨和软组织癌症，预后较差。其特征是 EWS 和 Ets 家族转录因子（最常见的是 FLI-1）之间的染色体易位。 EWS-FLI-1 融合占尤文肉瘤病例的 85%。 EWS-FLI-1 调节许多对肉瘤发生重要的基因的表达，可以转化 NIH3T3 和 C3H10T1/2 细胞，并且对于尤文肉瘤细胞的增殖和致瘤性是必需的，表明 EWS-FLI-1 是致病蛋白。在这里，我们报告 EWS-FLI-1 诱导 pappalysin-1 (PAPPA) 的表达，PAPPA 是一种细胞表面蛋白酶，可降解 IGF 结合蛋白 (IGFBP) 并增加 IGF 的生物利用度。 EWS-FLI-1 与 pappalysin-1 基因启动子结合并刺激 pappalysin-1 的表达，导致 IGFBP 降解并增强 IGF 信号传导。 pappalysin-1 的沉默强烈抑制贴壁依赖性和贴壁非依赖性生长以及尤文肉瘤细胞的异种移植致瘤性。这些结果表明，EWS-FLI-1 通过诱导 pappalysin-1 创建有利于 IGF 信号传导的细胞表面微环境，pappalysin-1 成为抑制尤文肉瘤中 IGF 信号传导的新靶点。
Ewing sarcoma is an aggressive cancer of bone and soft tissue in children with poor prognosis. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 fusion accounts for 85% of Ewing sarcoma cases. EWS-FLI-1 regulates the expression of a number of genes important for sarcomagenesis, can transform NIH3T3 and C3H10T1/2 cells, and is necessary for proliferation and tumorigenicity of Ewing sarcoma cells, suggesting that EWS-FLI-1 is the causative oncoprotein. Here we report that EWS-FLI-1 induces the expression of pappalysin-1 (PAPPA), a cell surface protease that degrades IGF binding proteins (IGFBPs) and increases the bioavailability of IGF. EWS-FLI-1 binds to the pappalysin-1 gene promoter and stimulates the expression of pappalysin-1, leading to degradation of IGFBPs and enhanced IGF signaling. Silencing of pappalysin-1 strongly inhibited anchorage-dependent and anchorage-independent growth as well as xenograft tumorigenicity of Ewing sarcoma cells. These results suggest that EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1, which emerged as a novel target to inhibit IGF signaling in Ewing sarcoma.