Analysis of miRNA profiles identified miR-196a as a crucial mediator of aberrant PI3K/AKT signaling in lung cancer cells.
Analysis of miRNA profiles identified miR-196a as a crucial mediator of aberrant PI3K/AKT signaling in lung cancer cells.
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DOI：
10.18632/oncotarget.13432
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Viglietto G
中科院分区：
文献类型：
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作者：
Guerriero I;D'Angelo D;Pallante P;Santos M;Scrima M;Malanga D;De Marco C;Ravo M;Weisz A;Laudanna C;Ceccarelli M;Falco G;Rizzuto A;Viglietto G
在包括肺癌在内的大多数人类癌症中观察到PI 3 K/AKT通路的过度活化。在此，我们研究了miRNAs作为激活的PI 3 K/AKT信号传导的下游靶点在非小细胞肺癌（NSCLC）中的作用。为此，在表达活性AKT 1（BEAS-AKT 1-E17 K）、活性PI 3 KCA（BEAS-PIK 3CA-E545 K）或具有沉默的PTEN（BEAS-shPTEN）的人肺上皮细胞（BEAS-2B）中进行miRNA谱分析。通过该分析鉴定了BEAS-AKT 1-E17 K、BEAS-PIK 3CA-E545 K和BEAS-shPTEN细胞共有的24种差异表达的miRNA，其中miR-196 a是最一致上调的miRNA。有趣的是，miR-196 a在人NSCLC衍生的细胞系（n=11）和原发性肺癌样品（n=28）中也显著过表达。通过在BEAS-2B和NCI-H460细胞中操纵miR-196 a的表达，我们获得了令人信服的证据，证明该miRNA在PI 3 K/AKT通路下游起作用，介导该通路在肺上皮细胞中发挥的一些增殖、促迁移和致瘤活性，可能通过调节FoxO 1、CDKN 1B（以下称为p27）和HOXA 9。
Hyperactivation of the PI3K/AKT pathway is observed in most human cancer including lung carcinomas. Here we have investigated the role of miRNAs as downstream targets of activated PI3K/AKT signaling in Non Small Cell Lung Cancer (NSCLC). To this aim, miRNA profiling was performed in human lung epithelial cells (BEAS-2B) expressing active AKT1 (BEAS-AKT1-E17K), active PI3KCA (BEAS-PIK3CA-E545K) or with silenced PTEN (BEAS-shPTEN). Twenty-four differentially expressed miRNAs common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells were identified through this analysis, with miR-196a being the most consistently up-regulated miRNA. Interestingly, miR-196a was significantly overexpressed also in human NSCLC-derived cell lines (n=11) and primary lung cancer samples (n=28). By manipulating the expression of miR-196a in BEAS-2B and NCI-H460 cells, we obtained compelling evidence that this miRNA acts downstream the PI3K/AKT pathway, mediating some of the proliferative, pro-migratory and tumorigenic activity that this pathway exerts in lung epithelial cells, possibly through the regulation of FoxO1, CDKN1B (hereafter p27) and HOXA9.