Ionizing radiation-inducible miR-494 promotes glioma cell invasion through EGFR stabilization by targeting p190B RhoGAP
Ionizing radiation-inducible miR-494 promotes glioma cell invasion through EGFR stabilization by targeting p190B RhoGAP
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DOI：
10.1016/j.bbamcr.2013.11.021
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发表时间：
2014-03-01
影响因子：
5.1
通讯作者：
Han, Young-Hoon
中科院分区：
文献类型：
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作者：
Kwak, Seo-Young;Yang, Ji-Sook;Han, Young-Hoon
MicroRNA (miRNA) 在肿瘤进展的各个阶段发挥着重要作用。我们之前已将 miR-494 鉴定为神经胶质瘤细胞系 U-251 中电离辐射 (IR) 诱导的 miRNA，观察到 miR-494 通过激活 MMP-2 来增强 U-251 细胞的侵袭。 miR-494 诱导的侵袭潜力伴随并依赖于表皮生长因子受体 (EGFR) 上调及其下游信号成分 Akt 和 ERK 的激活。 miR-494 对 EGFR 的上调涉及溶酶体蛋白周转的抑制。在测试的假定靶蛋白中，p190B RhoGAP (p190B) 被 miR-494 下调，其表达减少是 EGFR 表达增加的原因。使用含有 p190B 3'-非翻译区 (3'UTR) 的荧光素酶构建体进行的报告测定证实，p190B 是 miR-494 的直接靶标。通过小干扰 RNA (siRNA) 转染下调 p190B 与 miR-494 转染的结果非常相似，并显示 EGFR 表达、MMP-2 分泌和侵袭增加。 p190B 的异位表达抑制 miR-494 诱导的 EGFR 上调和侵袭促进，从而表明 p190B 耗竭对于 miR-494 的侵袭促进作用至关重要。总的来说，我们的结果表明 miR-494 具有新功能及其作为控制癌症治疗侵袭性的靶标的潜在应用。 (C) 2013 Elsevier B.V. 保留所有权利。
MicroRNAs (miRNAs) play an important role in various stages of tumor progression. miR-494, which we had previously identified as a miRNA induced by ionizing radiation (IR) in the glioma cell line U-251, was observed to enhance invasion of U-251 cells by activating MMP-2. The miR-494-induced invasive potential was accompanied by, and dependent on, epidermal growth factor receptor (EGFR) upregulation and the activation of its downstream signaling constituents, Akt and ERK. The upregulation of EGFR by miR-494 involved the suppression of lysosomal protein turnover. Among the putative target proteins tested, p190B RhoGAP (p190B) was downregulated by miR-494, and its reduced expression was responsible for the increase in EGFR expression. A reporter assay using a luciferase construct containing p190B 3'-untranslated region (3'UTR) confirmed that p190B is a direct target of miR-494. Downregulation of p190B by small interfering RNA (siRNA) transfection closely mimicked the outcomes of miR-494 transfection, and showed increased EGFR expression, MMP-2 secretion, and invasion. Ectopic expression of p190B suppressed the miR-494-induced EGFR upregulation and invasion promotion, thereby suggesting that p190B depletion is critical for the invasion-promoting action of miR-494. Collectively, our results suggest a novel function for miR-494 and its potential application as a target to control invasiveness in cancer therapy. (C) 2013 Elsevier B.V. All rights reserved.