Institute of Virology, Saarland University Medical School 66421, Homburg, Germany; Department of Microbiology, Faculty of Medicine, Khon Kaen University 40002, Khon Kaen, Thailand.
Cancer Med. 2012 Oct;1(2):141-55. doi: 10.1002/cam4.29. Epub 2012 Sep 18.
MicroRNAs (miRNAs) are short 18-23 nucleotide long noncoding RNAs that posttranscriptionally regulate gene expression by binding to mRNA. Our previous miRNA profiling of diffuse large B-cell lymphoma (DLBCL) revealed a mutation in the seed sequence of miR-142-3p. Further analysis now showed that miR-142 was mutated in 11 (19.64%) of the 56 DLBCL cases. Of these, one case had a mutation in both alleles, with the remainder being heterozygous. Four mutations were found in the mature miR-142-5p, four in the mature miR-142-3p, and three mutations affected the miR-142 precursor. Two mutations in the seed sequence redirected miR-142-3p to the mRNA of the transcriptional repressor ZEB2 and one of them also targeted the ZEB1 mRNA. However, the other mutations in the mature miR-142-3p did not influence either the ZEB1 or ZEB2 3' untranslated region (3' UTR). On the other hand, the mutations affecting the seed sequence of miR-142-3p resulted in a loss of responsiveness in the 3' UTR of the known miR-142-3p targets RAC1 and ADCY9. In contrast to the mouse p300 gene, the human p300 gene was not found to be a target for miR-142-5p. In one case with a mutation of the precursor, we observed aberrant processing of the miR-142-5p. Our data suggest that the mutations in miR-142 probably lead to a loss rather than a gain of function. This is the first report describing mutations of a miRNA gene in a large percentage of a distinct lymphoma subtype.
微小 RNA（miRNA）是一种短的 18-23 个核苷酸的非编码 RNA，通过与 mRNA 结合在转录后调节基因表达。我们之前对弥漫性大 B 细胞淋巴瘤（DLBCL）的 miRNA 谱分析显示 miR-142-3p 的种子序列发生了突变。进一步的分析表明，在 56 例 DLBCL 病例中有 11 例（19.64%）发生了 miR-142 突变。其中一个病例的两个等位基因都发生了突变，其余的则为杂合突变。在成熟的 miR-142-5p 中发现了四个突变，在成熟的 miR-142-3p 中发现了四个突变，在 miR-142 前体中发现了三个突变。种子序列中的两个突变使 miR-142-3p 重新定向到转录抑制因子 ZEB2 的 mRNA，其中一个也靶向 ZEB1 mRNA。然而，成熟 miR-142-3p 中的其他突变并没有影响 ZEB1 或 ZEB2 的 3'非翻译区（3'UTR）。另一方面，影响 miR-142-3p 种子序列的突变导致已知 miR-142-3p 靶标 RAC1 和 ADCY9 的 3'UTR 失去反应性。与小鼠 p300 基因不同，人类 p300 基因不是 miR-142-5p 的靶标。在一个前体发生突变的病例中，我们观察到 miR-142-5p 的异常加工。我们的数据表明，miR-142 的突变可能导致功能丧失而不是获得。这是第一个描述在一个明确的淋巴瘤亚型中有很大比例的 miRNA 基因发生突变的报道。
