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首页> 外文期刊>Molecular and Cellular Biology >Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis
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Inhibition of Nonsense-Mediated RNA Decay by the Tumor Microenvironment Promotes Tumorigenesis

机译：肿瘤微环境抑制无意义介导的RNA衰变促进肿瘤发生。

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While nonsense-mediated RNA decay (NMD) is an established mechanism to rapidly degrade select transcripts, the physiological regulation and biological significance of NMD are not well characterized. We previously demonstrated that NMD is inhibited in hypoxic cells. Here we show that the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) translation initiation factor by a variety of cellular stresses leads to the inhibition of NMD and that eIF2α phosphorylation and NMD inhibition occur in tumors. To explore the significance of this NMD regulation, we used an unbiased approach to identify approximately 750 NMD-targeted mRNAs and found that these mRNAs are overrepresented in stress response and tumor-promoting pathways. Consistent with these findings, the inhibition of NMD promotes cellular resistance to endoplasmic reticulum stress and encourages tumor formation. The transcriptional and translational regulations of gene expression by the microenvironment are established mechanisms by which tumor cells adapt to stress. These data indicate that NMD inhibition by the tumor microenvironment is also an important mechanism to dynamically regulate genes critical for the response to cellular stress and tumorigenesis.
机译：虽然无意义介导的RNA衰变（NMD）是一种快速降解所选转录本的既定机制，但NMD的生理调节和生物学意义尚未得到很好的表征。我们先前证明NMD在缺氧细胞中受到抑制。在这里，我们显示了各种细胞应激对真核起始因子2（eIF2α）翻译起始因子α亚基的磷酸化导致了NMD的抑制，而eIF2α的磷酸化和NMD抑制在肿瘤中发生。为了探索这种NMD调控的重要性，我们使用了一种无偏倚的方法来识别大约750个NMD靶向的mRNA，并发现这些mRNA在应激反应和肿瘤促进途径中的表达过多。与这些发现一致，NMD的抑制促进细胞对内质网应激的抵抗并促进肿瘤形成。微环境中基因表达的转录和翻译调控是肿瘤细胞适应应激的既定机制。这些数据表明，肿瘤微环境对NMD的抑制也是动态调节对细胞应激和肿瘤发生的反应至关重要的基因的重要机制。

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