Background RNA editing generates modifications to the RNA sequences, thereby increasing protein diversity and shaping various layers of gene regulation. Recent studies have revealed global shifts in editing levels across many cancer types, as well as a few specific mechanisms implicating individual sites in tumorigenesis or metastasis. However, most tumor-associated sites, predominantly in noncoding regions, have unknown functional relevance. Results Here, we carry out integrative analysis of RNA editing profiles between epithelial and mesenchymal tumors, since epithelial-mesenchymal transition is a key paradigm for metastasis. We identify distinct editing patterns between epithelial and mesenchymal tumors in seven cancer types using TCGA data, an observation further supported by single-cell RNA sequencing data and ADAR perturbation experiments in cell culture. Through computational analyses and experimental validations, we show that differential editing sites between epithelial and mesenchymal phenotypes function by regulating mRNA abundance of their respective genes. Our analysis of RNA-binding proteins reveals ILF3 as a potential regulator of this process, supported by experimental validations. Consistent with the known roles of ILF3 in immune response, epithelial-mesenchymal differential editing sites are enriched in genes involved in immune and viral processes. The strongest target of editing-dependent ILF3 regulation is the transcript encoding PKR, a crucial player in immune and viral response. Conclusions Our study reports widespread differences in RNA editing between epithelial and mesenchymal tumors and a novel mechanism of editing-dependent regulation of mRNA abundance. It reveals the broad impact of RNA editing in cancer and its relevance to cancer-related immune pathways.

中文翻译：

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癌症中的 RNA 编辑影响免疫反应途径中 mRNA 的丰度

背景 RNA 编辑会对 RNA 序列进行修改，从而增加蛋白质多样性并塑造不同层次的基因调控。最近的研究揭示了许多癌症类型的编辑水平的全球变化，以及涉及肿瘤发生或转移中各个位点的一些特定机制。然而，大多数肿瘤相关位点（主要位于非编码区）具有未知的功能相关性。结果在这里，我们对上皮性肿瘤和间质性肿瘤之间的RNA编辑谱进行综合分析，因为上皮-间质转化是转移的关键范例。我们使用 TCGA 数据识别了七种癌症类型中上皮性肿瘤和间质性肿瘤之间的不同编辑模式，这一观察结果得到了单细胞 RNA 测序数据和细胞培养中 ADAR 扰动实验的进一步支持。通过计算分析和实验验证，我们表明上皮和间质表型之间的差异编辑位点通过调节各自基因的 mRNA 丰度发挥作用。我们对 RNA 结合蛋白的分析表明，ILF3 是该过程的潜在调节剂，并得到实验验证的支持。与 ILF3 在免疫反应中的已知作用一致，上皮-间质差异编辑位点富含参与免疫和病毒过程的基因。编辑依赖性 ILF3 调节的最强目标是编码 PKR 的转录本，PKR 在免疫和病毒反应中发挥着关键作用。结论 我们的研究报告了上皮肿瘤和间质肿瘤之间 RNA 编辑的广泛差异，以及 mRNA 丰度的编辑依赖性调节的新机制。它揭示了 RNA 编辑在癌症中的广泛影响及其与癌症相关免疫途径的相关性。