Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer.
Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer.
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DOI：
10.1158/0008-5472.can-22-0240
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发表时间：
2022-10-17
期刊：
影响因子：
11.2
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中科院分区：
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mirna的表转录组学研究为癌症领域增加了一层新的复杂性。尽管人们对腺苷-肌苷（A-to-I） miRNA编辑和改变miRNA亚型的选择性切割的兴趣迅速增长，但在癌症中对这两种修饰的同时评估仍然缺失。在这里，我们同时分析了多种miRNA修饰类型，包括A-to-I miRNA编辑和转移的miRNA亚型，在来自癌症基因组图谱和治疗适用研究生成有效治疗数据集的38个不同癌症队列的bb10000个成人和儿童肿瘤样本中。研究了规范mirna与广泛miRNAome在表达、聚类、失调和预后立场方面的差异。规范mirna和修饰mirna的结合提高了聚类结果的质量，概述了队列中独特的临床病理特征。某些修饰的mirna在癌症中表现出与标准mirna相反的表达，潜在地影响了它们的靶标和功能。最后，通过实验验证了移位和编辑的miRNA异构体可以直接结合和抑制一个独特的靶标。这些发现概述了超越每个miRNA臂一个成熟miRNA的既定范式来阐明与癌症进展相关的新机制的重要性。
Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in >13,000 adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments datasets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathological features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression.