MCM7 and its hosted miR-25, 93 and 106b cluster elicit YAP/TAZ oncogenic activity in lung cancer
MCM7 and its hosted miR-25, 93 and 106b cluster elicit YAP/TAZ oncogenic activity in lung cancer
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DOI：
10.1093/carcin/bgw110
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发表时间：
2017-01-01
期刊：
影响因子：
4.7
通讯作者：
Blandino, Giovanni
中科院分区：
文献类型：
--
作者：
Lo Sardo, Federica;Forcato, Mattia;Blandino, Giovanni
肺癌是全球癌症死亡的首要原因，Hippo 通路转录共激活因子 YAP/TAZ 在这方面具有促癌作用。为了了解 YAP/TAZ 在不同系统中引发致癌作用的机制，许多研究都集中在参与细胞增殖/存活和迁移调节的 YAP/TAZ 靶基因。然而，关于 YAP/TAZ 在 microRNA 调节中的作用的证据很少，而越来越多的证据支持 microRNA 在主要致癌过程中的作用。在这里，我们证明 YAP/TAZ 能够调节非小细胞肺癌 (NSCLC) 细胞系中的几种 microRNA。具体来说，我们重点关注了 MCM7 基因中的三种致癌 microRNA（miR-25、93 和 106b）簇，与正常组织相比，它们在肺肿瘤中过度表达。此外，在乳腺癌和头颈肿瘤诊断中也观察到类似的行为，它们显示出预后作用。在 NSCLC 细胞中，YAP/TAZ 诱导 MCM7 基因及其宿主 miR 的转录，从而通过 p21 细胞周期调节因子的转录后抑制促进细胞增殖。因此，与正常组织相比，p21 在肺肿瘤中维持在较低水平。相反，在 YAP/TAZ 干扰或用他汀类西立伐他汀治疗后，其表达在 NSCLC 细胞中恢复。总之，我们为一种新的调节机制提供了证据，该机制通过调节由一个基因和三个宿主 microRNA 组成的生物基因座来支持 YAP/TAZ 因子的促肿瘤发生功能。
Lung cancer is the first cause of cancer death worldwide and the Hippo pathway transcriptional coactivators YAP/TAZ have a pro-oncogenic role in this context. In order to understand the mechanisms through which YAP/TAZ elicit their oncogenic role in different systems, many studies are focused on YAP/TAZ target genes involved in the regulation of cell proliferation/survival and migration. However, there is scarce evidence on the role of YAP/TAZ in microRNA regulation while there is increasing evidence supporting the role of microRNAs in the main oncogenic processes. Here, we showed that YAP/TAZ were able to regulate several microRNAs in non-small cell lung cancer (NSCLC) cell lines. In detail, we focused on a cluster of three oncogenic microRNAs (miR-25, 93 and 106b) hosted in the MCM7 gene that were overexpressed in lung tumors compared to normal tissues. In addition, similar behavior was observed in breast cancer and head and neck tumor casuistries, where they showed a prognostic role. In NSCLC cells, YAP/TAZ induced the transcription of the MCM7 gene and its hosted miRs, thereby promoting cell proliferation through the post-transcriptional inhibition of the p21 cell cycle regulator. Accordingly, p21 was maintained at low levels in lung tumors compared to normal tissues. Conversely, its expression was restored in NSCLC cells upon YAP/TAZ interference or upon treatment with the statin cerivastatin. In summary, we provide evidence for a novel mechanism of modulation supporting the protumorigenic functions of the YAP/TAZ factors through the modulation of a bioncogenic locus consisting of one gene and three hosted microRNAs.