Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
IUBMB Life. 2023 Jul;75(7):566-579. doi: 10.1002/iub.2710. Epub 2023 Mar 27.
Long noncoding RNAs (lncRNAs) are emerging players in cancer and they entail potential as prognostic biomarkers or therapeutic targets. Earlier studies have identified somatic mutations in lncRNAs that are associated with tumor relapse after therapy, but the underlying mechanisms behind these associations remain unknown. Given the relevance of secondary structure for the function of some lncRNAs, some of these mutations may have a functional impact through structural disturbance. Here, we examined the potential structural and functional impact of a novel A > G point mutation in NEAT1 that has been recurrently observed in tumors of colorectal cancer patients experiencing relapse after treatment. Here, we used the nextPARS structural probing approach to provide first empirical evidence that this mutation alters NEAT1 structure. We further evaluated the potential effects of this structural alteration using computational tools and found that this mutation likely alters the binding propensities of several NEAT1-interacting miRNAs. Differential expression analysis on these miRNA networks shows upregulation of Vimentin, consistent with previous findings. We propose a hybrid pipeline that can be used to explore the potential functional effects of lncRNA somatic mutations.
长链非编码 RNA（lncRNA）是癌症中的新兴参与者，它们具有作为预后生物标志物或治疗靶点的潜力。早期的研究已经确定了 lncRNA 的体细胞突变，这些突变与治疗后肿瘤复发有关，但这些关联背后的潜在机制尚不清楚。鉴于二级结构对某些 lncRNA 功能的重要性，其中一些突变可能通过结构干扰产生功能影响。在这里，我们研究了在接受治疗后复发的结直肠癌患者的肿瘤中反复观察到的 NEAT1 中一种新型 A > G 点突变的潜在结构和功能影响。在这里，我们使用 nextPARS 结构探测方法首次提供了经验证据，证明该突变改变了 NEAT1 的结构。我们进一步使用计算工具评估了这种结构改变的潜在影响，发现该突变可能改变了几个与 NEAT1 相互作用的 miRNA 的结合倾向。对这些 miRNA 网络的差异表达分析显示，波形蛋白上调，与先前的发现一致。我们提出了一种混合管道，可以用于探索 lncRNA 体细胞突变的潜在功能影响。
