Poly(A)-specific RNase (PARN) generates and regulates miR-125a-5p 3'-isoforms, displaying an altered expression in breast cancer.
Poly(A)-specific RNase (PARN) generates and regulates miR-125a-5p 3'-isoforms, displaying an altered expression in breast cancer.
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Poly(A) 特异性 RNase (PARN) 生成并调节 miR-125a-5p 3-亚型，在乳腺癌中表现出表达改变。
DOI：
10.1038/s41392-024-01795-3
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发表时间：
2024
影响因子：
39.3
通讯作者：
Croce,CarloM
中科院分区：
文献类型：
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作者：
Tomasello,Luisa;Holub,ShoshanahM;Nigita,Giovanni;Distefano,Rosario;Croce,CarloM
MicroRNA（miRNAs）是一类对转录后基因调控至关重要的小分子非编码RNA，由Drosha和Dicer从原始的miRNA转录本中加工而成。1下一代测序的最新进展强调了由替代加工、RNA编辑或转录后修饰产生的miRNA异构体（isomiR）的存在。1 IsomiRs可以在癌症等疾病中具有独特的靶向偏好和诊断价值。1核酸外切酶是切割RNA或DNA末端的酶，在miRNA调控中起着至关重要的作用。2.它们控制miRNA的稳定性和生物发生。2我们全面分析了来自癌症基因组图谱计划（TCGA）和产生有效治疗的治疗适用研究（TARGET）的38个不同队列的13，000多个癌症样本中的典型和修饰的miRNA。19种miR-125 a-5 p 3L-亚型在17种癌症类型中出现显著失调。在至少一种条件（正常或肿瘤）下的所有比较中，额外的过滤保留了具有高于miR-125- 5 p 3L-同种型的第25百分位数的表达的miRNA同种型。9种miRNA亚型中只有4种在过滤后存活，特别是miR-125 a-5 p（0| miR-125a-5p（0| miR-125a-5p（0|-2）和miR-125 a-5 p（0|-3），仅miR-125 a-5 p（0| miR-125a-5p（0|-2）和miR-125 a-5 p（0|-3）在至少50%的比较中显著失调。七个TCGA组群在肿瘤与正常比较中呈现所有三种亚型显著失调（图1a）。值得注意的是，在7个队列中的6个中，两种较短的同种型的表达（0|-2）和（0|-3）在癌症中出现下调，而数据库注释的分子miR-125 a-5 p（0| 0），在肿瘤样品中更高（图la）。我们研究了乳腺癌（TCGA-BRCA）中的这些亚型，因为miR-125 a-5 p被认为是这种类型癌症的肿瘤抑制因子。3为了阐明这些亚型是否具有不同的作用，我们最初通过RNA免疫沉淀分析证实argonaute RISC催化组分2（AGO 2）与所有三种分子结合，4从而表明所有三种microRNA亚型可能具有潜在的功能。为了确定它们是否具有拮抗或支持功能，我们分析了属于TCGA-BRCA队列的患者中失调的基因，其中每个miR-125 a-5 p亚型的表达最高（第75百分位）和最低（第25百分位）（图1 B，左图）。从该分析中获得的数据随后用于免疫途径分析（IPA），4其强调了miR-125 a-5 p的较短同种型参与关键细胞周期蛋白的调控。4
MicroRNAs (miRNAs) are small non-coding RNAs crucial for post-transcriptional gene regulation, processed from primary miRNA transcripts by Drosha and Dicer. 1 Latest advancements in Next Generation Sequencing highlighted the existence of miRNA isoforms (isomiRs) resulting from alternative processing, RNA editing, or post-transcriptional modifications. 1 IsomiRs can have distinct target preferences and diagnostic value in diseases like cancer. 1 Exonucleases are enzymes cleaving RNA or DNA ends, playing a vital role in miRNA regulation. 2 They control miRNA stability and biogenesis. 2We comprehensively profiled canonical and modified miRNAs in over 13,000 cancer samples across 38 distinct cohorts from The Cancer Genome Atlas Program (TCGA) and The Therapeutically Applicable Research to Generate Effective Treatments (TARGET). 1 Nine miR-125a-5p 3L-isoforms appeared to be significantly dysregulated in 17 cancer types. An additional filtering retained miRNA isoforms having expression above the 25th percentile of miR-125-5p 3L-isoforms in all comparisons in at least one condition (normal or tumor). Only four out of nine miRNA isoforms survived the filtering, specifically miR-125a-5p (0| 0), miR-125a-5p (0|-1), miR-125a-5p (0|-2), and miR-125a-5p (0|-3), with only miR-125a-5p (0| 0), miR-125a-5p (0|-2), and miR-125a-5p (0|-3) being significantly dysregulated in at least 50% of the comparisons. Seven TCGA-cohorts presented all three isoforms significantly dysregulated in the tumor vs. normal comparison (Fig. 1 a). Notably, in six out of seven cohorts, the expression of the two shorter isoforms (0|-2) and (0|-3) appeared downregulated in cancer, while the expression of the database-annotated molecule, miR-125a-5p (0| 0), was higher in tumor samples (Fig. 1 a). We investigated these isoforms in breast cancer (TCGA-BRCA), given that miR-125a-5p is considered a tumor suppressor in this type of cancer. 3 Intending to elucidate whether these isoforms could have distinct roles, we initially confirmed through RNA-Immunoprecipitation analysis that argonaute RISC catalytic component 2 (AGO2) binds to all three molecules, 4 thus suggesting that all three microRNA isoforms may potentially be functional. To determine whether they have antagonistic or supportive functions, we analyzed the genes dysregulated in patients belonging to the TCGA-BRCA cohort with the highest (75th percentile) and the lowest expression (25th percentile) of each miR-125a-5p isoform (Fig. 1 b, left panel). The data obtained from this analysis were subsequently employed for an Ingenuity Pathway Analysis (IPA), 4 which highlighted the involvement of the shorter isoforms of miR-125a-5p in the regulation of key cell cycle proteins. 4