Induction of tenascin‐C by tumor‐specific EWS‐ETS fusion genes
Induction of tenascin‐C by tumor‐specific EWS‐ETS fusion genes
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DOI：
10.1002/gcc.10153
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发表时间：
2003-03
期刊：
影响因子：
3.5
通讯作者：
G. Watanabe;H. Nishimori;H. Irifune;Y. Sasaki;S. Ishida;H. Zembutsu;Toshihiro Tanaka;S. Kawaguchi;T. Wada;J. Hata;M. Kusakabe;Koichi Yoshida;Yusuke Nakamura;T. Tokino
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文献类型：
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作者：
G. Watanabe;H. Nishimori;H. Irifune;Y. Sasaki;S. Ishida;H. Zembutsu;Toshihiro Tanaka;S. Kawaguchi;T. Wada;J. Hata;M. Kusakabe;Koichi Yoshida;Yusuke Nakamura;T. Tokino
尤文氏肉瘤（ES）和周围原始神经外胚层肿瘤（PNETs）与染色体易位相关，导致EWS的氨基端与ETS转录因子（最常见的是FLI1或ERG）的DNA结合域融合。虽然以前的报道表明这些嵌合体蛋白可能作为异常转录因子，但它们的下游靶点尚未完全阐明。为了确定这些EWS - ETS融合蛋白的下游靶点，我们通过逆转录病毒转导将EWS - ETS融合构建物导入人纤维肉瘤细胞系HT - 1080。在这里，我们报告了在表达EWS‐ets的细胞中，Tenascin‐C （TNC）被诱导到显著高于表达正常ets的细胞。此外，通过使用反义cDNA表达载体，我们发现内源性TNC mRNA和蛋白的表达随着EWS‐FLI1融合蛋白表达的衰减而协同降低。染色质免疫沉淀试验显示TNC启动子与EWS - FLI1融合蛋白在体内直接相互作用。此外，荧光素酶报告基因分析显示，EWS‐ETS通过TNC启动子中的四个ETS结合位点上调TNC基因。在ES细胞系（6个中的3个）和原发肿瘤（6个中的4个）中观察到高水平的TNC表达。结合先前的研究表明TNC表达参与了几种肿瘤类型的侵袭性和恶性表型，我们的数据表明EWS‐ETS的致癌作用可能部分通过上调TNC表达来介导。©2003 Wiley‐Liss, Inc。
Ewing sarcoma (ES) and peripheral primitive neuroectodermal tumors (PNETs) are associated with a chromosomal translocation resulting in a fusion of the amino‐terminus of EWS with the DNA‐binding domain of an ETS transcription factor (most commonly FLI1 or ERG). Although previous reports suggested that these chimera proteins would act as aberrant transcription factors, their downstream targets have not been fully elucidated. To identify downstream targets of these EWS‐ETS fusion proteins, we introduced EWS‐ETS fusion constructs into a human fibrosarcoma cell line, HT‐1080, by retroviral transduction. Here we report that Tenascin‐C (TNC) is induced to a significantly higher level in cells expressing EWS‐ETSs than in cells expressing normal ETSs. Furthermore, through use of an antisense cDNA expression vector we show that expression of endogenous TNC mRNA and protein were reduced coordinately with attenuation of EWS‐FLI1 fusion protein expression. A chromatin immunoprecipitation assay showed direct interaction between the TNC promoter and the EWS‐FLI1 fusion protein in vivo. In addition, a luciferase reporter assay revealed that EWS‐ETSs upregulated the TNC gene through four ETS binding sites in the TNC promoter. High levels of TNC expression were observed in a subset of ES cell lines (3 of 6) and primary tumors (4 of 6). Together with previous studies showing that TNC expression is involved in the invasive and malignant phenotype of several tumor types, our data suggest that the oncogenic effect of EWS‐ETS may be mediated in part by upregulating of TNC expression. © 2003 Wiley‐Liss, Inc.