Zhang Yuanfu, Han Peng, Guo Qiuyan, Hao Yangyang, Qi Yue, Xin Mengyu, Zhang Yafang, Cui Binbin, Wang Peng
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
Front Cell Dev Biol. 2021 May 17;9:658346. doi: 10.3389/fcell.2021.658346. eCollection 2021.
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 -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.
竞争性内源性RNA（ceRNA）是通过竞争共享微小RNA（miRNA）的结合而相互交流并共同调节的转录本。长链非编码RNA（lncRNA）作为ceRNA的一种类型，构成了由miRNA反应元件（MRE）决定的竞争性调控网络。lncRNA MRE中的突变会破坏其原有的调控途径。研究lncRNA体细胞突变对ceRNA机制的影响可以阐明肿瘤机制，并有助于精准医学的发展。在此，我们利用从癌症基因组图谱（TCGA）收集的体细胞突变谱，来描述lncRNA体细胞突变在33种癌症的ceRNA调控网络中的作用。由TargetScan和miRanda鉴定出的31,560个突变位点影响了70,811条ceRNA调控途径的平衡。根据突变频率将推定的突变分为高频或低频。多变量多元回归显示，六种癌症类型中的162个高频突变通过ceRNA机制对靶mRNA（ceM）的表达水平有显著影响。通过学生t检验验证了多种癌症中干扰1624个ceM的低频突变，表明致癌基因表达水平变化的显著机制。涉及ceM的致癌信号通路研究表明多种癌症具有功能异质性。此外，我们发现干扰与患者生存相关的ceM的lncRNA有作为生物标志物的潜力。我们的总体研究结果揭示了体细胞突变在干扰ceM表达和影响肿瘤异质性方面的个体差异。
