MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4.
MiR-150 promotes cellular metastasis in non-small cell lung cancer by targeting FOXO4.
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MiR-150 通过靶向 FOXO4 促进非小细胞肺癌细胞转移
DOI：
10.1038/srep39001
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发表时间：
2016-12-15
影响因子：
4.6
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Li H;Ouyang R;Wang Z;Zhou W;Chen H;Jiang Y;Zhang Y;Li H;Liao M;Wang W;Ye M;Ding Z;Feng X;Liu J;Zhang B
先前的研究表明，microRNA-150（miR-150）的失调与人类非小细胞肺癌（NSCLC）细胞的异常增殖有关。然而，miR-150是否在NSCLC细胞转移中具有关键作用尚不清楚。在这里，我们揭示了miR-150在NSCLC中通过下调FOXO 4调节上皮-间质转化（EMT）中的关键促转移作用。在体外，miR-150靶向FOXO 4 mRNA的3′UTR区域，从而负调控其表达。在临床上，miR-150的表达在转移性NSCLC细胞系和临床标本中频繁上调。因此，FOXO 4在NSCLC细胞系和临床标本中经常下调。功能研究表明，miR-150的异位表达在体外和小鼠异种移植模型中增强肿瘤细胞转移，并触发NSCLC细胞中的EMT样变化（包括E-钙粘蛋白抑制、N-钙粘蛋白和波形蛋白诱导以及间充质形态）。相应地，FOXO 4敲低表现出类似于miR-150过表达的促转移和分子效应。此外，受FOXO 4调控的NF-κB/snail/YY 1/RKIP通路可能参与了miR-150诱导的EMT事件。同时敲除miR-150和FOXO 4消除了由单独敲除miR-150引起的表型和分子效应。因此，我们的研究提供了先前未鉴定的miR-150在NSCLC中的促转移作用和机制。
Previous studies have shown that dysregulation of microRNA-150 (miR-150) is associated with aberrant proliferation of human non-small cell lung cancer (NSCLC) cells. However, whether miR-150 has a critical role in NSCLC cell metastasis is unknown. Here, we reveal that the critical pro-metastatic role of miR-150 in the regulation of epithelial-mesenchymal-transition (EMT) through down-regulation of FOXO4 in NSCLC. In vitro, miR-150 targets 3′UTR region of FOXO4 mRNA, thereby negatively regulating its expression. Clinically, the expression of miR-150 was frequently up-regulated in metastatic NSCLC cell lines and clinical specimens. Contrarily, FOXO4 was frequently down-regulated in NSCLC cell lines and clinical specimens. Functional studies show that ectopic expression of miR-150 enhanced tumor cell metastasis in vitro and in a mouse xenograft model, and triggered EMT-like changes in NSCLC cells (including E-cadherin repression, N-cadherin and Vimentin induction, and mesenchymal morphology). Correspondingly, FOXO4 knockdown exhibited pro-metastatic and molecular effects resembling the effect of miR-150 over-expression. Moreover, NF-κB/snail/YY1/RKIP circuitry regulated by FOXO4 were likely involved in miR-150-induced EMT event. Simultaneous knockdown of miR-150 and FOXO4 abolished the phenotypic and molecular effects caused by individual knockdown of miR-150. Therefore, our study provides previously unidentified pro-metastatic roles and mechanisms of miR-150 in NSCLC.
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