Oncogenic Landscape of Somatic Mutations Perturbing Pan-Cancer lncRNA-ceRNA Regulation.
Oncogenic Landscape of Somatic Mutations Perturbing Pan-Cancer lncRNA-ceRNA Regulation.
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体细胞突变的致癌景观扰乱泛癌 lncRNA-ceRNA 调控
DOI：
10.3389/fcell.2021.658346
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Zhang Y;Han P;Guo Q;Hao Y;Qi Y;Xin M;Zhang Y;Cui B;Wang P
竞争性内源性RNA（ceRNA）是通过竞争共享microRNA（miRNAs）的结合而相互通信并共同调节的转录物。长链非编码RNA（lncRNA）作为ceRNA的一种，构成了由miRNA应答元件（MREs）决定的竞争性调控网络。lncRNA MRE中的突变使其原始调节途径不稳定。研究lncRNA体细胞突变对ceRNA机制的影响，可以阐明肿瘤机制，有助于精准医学的发展。在这里，我们使用从TCGA收集的体细胞突变谱来表征lncRNA体细胞突变在33种癌症的ceRNA调控网络中的作用。TargetScan和米兰达发现的31，560个突变位点影响了70，811个ceRNA调控通路的平衡。根据突变频率将推定突变分类为高或低。多变量多元回归显示，6种癌症类型中的162种高频突变通过ceRNA机制对靶mRNA（ceM）的表达水平产生显著影响。干扰1624 ceM的多种癌症中的低频率突变已通过Student's t检验验证，表明致癌基因表达水平变化的重要机制。涉及ceMs的致癌信号通路研究表明多种癌症的功能异质性。此外，我们发现，干扰与患者生存相关的细胞的lncRNA具有作为生物标志物的潜力。我们的集体研究结果揭示了干扰ceM表达和影响肿瘤异质性的体细胞突变的个体差异。
Competing endogenous RNAs (ceRNA) are transcripts that communicate with and co-regulate each other by competing for the binding of shared microRNAs (miRNAs). Long non-coding RNAs (lncRNAs) as a type of ceRNA constitute a competitive regulatory network determined by miRNA response elements (MREs). Mutations in lncRNA MREs destabilize their original regulatory pathways. Study of the effects of lncRNA somatic mutations on ceRNA mechanisms can clarify tumor mechanisms and contribute to the development of precision medicine. Here, we used somatic mutation profiles collected from TCGA to characterize the role of lncRNA somatic mutations in the ceRNA regulatory network in 33 cancers. The 31,560 mutation sites identified by TargetScan and miRanda affected the balance of 70,811 ceRNA regulatory pathways. Putative mutations were categorized as high or low based on mutation frequencies. Multivariate multiple regression revealed a significant effect of 162 high-frequency mutations in six cancer types on the expression levels of target mRNAs (ceMs) through the ceRNA mechanism. Low-frequency mutations in multiple cancers perturbing 1624 ceM have been verified by Student’s t-test, indicating a significant mechanism of changes in the expression level of oncogenic genes. Oncogenic signaling pathway studies involving ceMs indicated functional heterogeneity of multiple cancers. Furthermore, we identified that lncRNA, perturbing ceMs associated with patient survival, have potential as biomarkers. Our collective findings revealed individual differences in somatic mutations perturbing ceM expression and impacting tumor heterogeneity.
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