Regulation of Epidermal Growth Factor Receptor Signaling in Human Cancer Cells by MicroRNA-7
Regulation of Epidermal Growth Factor Receptor Signaling in Human Cancer Cells by MicroRNA-7
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DOI：
10.1074/jbc.m804280200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Leedman, Peter J.
中科院分区：
文献类型：
--
作者：
Webster, Rebecca J.;Giles, Keith M.;Leedman, Peter J.
表皮生长因子受体（EGFR）在癌症中经常过表达，是一个重要的治疗靶点。microrna的异常表达和功能与肿瘤发生有关。生物信息学预测表明，人类EGFR mRNA 3'-非翻译区包含三个microRNA-7 （miR-7）靶点，这些靶点在哺乳动物中并不保守。我们发现miR-7通过三个位点中的两个下调癌细胞系（肺癌、乳腺癌和胶质母细胞瘤）中EGFR mRNA和蛋白的表达，诱导细胞周期阻滞和细胞死亡。由于miR-7被证明可以降低EGFR mRNA的表达，我们使用微阵列分析来鉴定miR-7的其他mRNA靶点。其中包括Raf1和其他多个参与EGFR信号传导和肿瘤发生的基因。此外，miR-7在不同的癌细胞系中减弱了蛋白激酶B （Akt）和细胞外信号调节激酶1/2的激活，这是EGFR信号传导的两个关键效应物。这些数据证实了miR-7在控制mRNA表达中的重要作用，并表明miR-7在多种人类癌细胞类型中具有协调调节EGFR信号传导的能力。
The epidermal growth factor receptor (EGFR) is frequently overexpressed in cancer and is an important therapeutic target. Aberrant expression and function of microRNAs have been associated with tumorigenesis. Bioinformatic predictions suggest that the human EGFR mRNA 3'-untranslated region contains three microRNA-7 (miR-7) target sites, which are not conserved across mammals. We found that miR-7 down-regulates EGFR mRNA and protein expression in cancer cell lines (lung, breast, and glioblastoma) via two of the three sites, inducing cell cycle arrest and cell death. Because miR-7 was shown to decrease EGFR mRNA expression, we used microarray analysis to identify additional mRNA targets of miR-7. These included Raf1 and multiple other genes involved in EGFR signaling and tumorigenesis. Furthermore, miR-7 attenuated activation of protein kinase B (Akt) and extracellular signal-regulated kinase 1/2, two critical effectors of EGFR signaling, in different cancer cell lines. These data establish an important role for miR-7 in controlling mRNA expression and indicate that miR-7 has the ability to coordinately regulate EGFR signaling in multiple human cancer cell types.