EGFR Promotes Lung Tumorigenesis by Activating miR-7 through a Ras/ERK/Myc Pathway That Targets the Ets2 Transcriptional Repressor ERF
EGFR Promotes Lung Tumorigenesis by Activating miR-7 through a Ras/ERK/Myc Pathway That Targets the Ets2 Transcriptional Repressor ERF
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DOI：
10.1158/0008-5472.can-10-0638
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Cheng-Wen
中科院分区：
文献类型：
--
作者：
Chou, Yu-Ting;Lin, Hua-Heng;Wu, Cheng-Wen
微小RNA（miRNA）介导由表皮生长因子受体（EGFR）激活触发的不同基因调控途径，其通常发生在预后不良的肺癌中。在这项研究中，我们报告的发现和机制表征的miRNA miR-7作为一种致癌的“oncomiR”和它的作用，作为一个关键的调解人的EGFR信号在肺癌细胞。EGFR激活或Ras以及c-Myc的异位表达以细胞外信号调节激酶（ERK）依赖性方式刺激miR-7表达，表明EGFR通过Ras/ERK/Myc途径诱导miR-7表达。为了支持这种可能性，c-Myc与miR-7启动子结合并增强其活性。异位miR-7促进肺癌细胞的细胞生长和肿瘤形成，显著增加原位植入肺癌的裸鼠宿主的死亡率。定量蛋白质组学分析显示，miR-7降低了Ets 2转录抑制因子ERF的水平，发现ERF的编码序列含有miR-7互补序列。事实上，异位miR-7抑制了野生型而非沉默突变编码序列的ERF信息的产生，并且异位miR-7挽救了野生型而非突变ERF产生的生长停滞。总之，这些结果确定ERF是肺癌中miR-7的直接靶点。我们的研究结果表明，miR-7可能是EGFR介导的肿瘤发生的重要调节剂，具有潜在的应用前景，作为一种新的预后生物标志物和治疗靶点在肺癌。Cancer Res; 70（21）; 8822-31. (C)2010年AACR。
MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic "oncomiR" and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer. Cancer Res; 70(21); 8822-31. (C) 2010 AACR.