Suppression of microRNA-9 by mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity.
Suppression of microRNA-9 by mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity.
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DOI：
10.1158/0008-5472.can-13-2117
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发表时间：
2014-03-01
期刊：
影响因子：
11.2
通讯作者：
Cavenee WK
中科院分区：
文献类型：
--
作者：
Gomez GG;Volinia S;Croce CM;Zanca C;Li M;Emnett R;Gutmann DH;Brennan CW;Furnari FB;Cavenee WK
EGF受体（EGFR）在胶质母细胞瘤（GBM）中扩增和突变，其常见突变（ΔEGFR，也称为EGFRvIII）具有多种促进生长和抑制死亡的活性，从而赋予强烈的肿瘤增强效应。这种活性范围向我们表明，ΔEGFR可能通过多效性效应物发挥其影响，我们假设microRNA（miRs）可能发挥这种功能。在这里，我们报告了ΔEGFR通过已知激活的Ras/PI 3 K/AKT轴特异性抑制一种这样的miR，即miR-9。相应地，miR-9的表达拮抗ΔEGFR赋予的肿瘤生长优势。沉默FOXP 1（一种miR-9靶标）可抑制Δ EGFR依赖性肿瘤生长，相反，由于miR-9抑制，FOXP 1的去抑制可增加致瘤性。在缺乏致癌ΔEGFR信号传导的情况下，FOXP 1足以增加肿瘤生长。这些发现的重要性被我们的发现所强调，在131例GBM患者的队列中，FOXP 1高表达预测生存率低。总的来说，这些数据表明了一种新的调节机制，通过这种机制，miR-9的ΔEGFR抑制上调FOXP 1以增加致瘤性。
The EGF receptor (EGFR) is amplified and mutated in glioblastoma (GBM) where its common mutation (ΔEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ΔEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs (miRs) might serve such a function. Here, we report that ΔEGFR specifically suppresses one such miR, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ΔEGFR. Silencing of FOXP1, a miR-9 target, inhibits ΔEGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ΔEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 GBM patients. Collectively, these data suggest a novel regulatory mechanism by which ΔEGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity.