Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, The Ohio State University, Columbus, OH 43210, USA.
Sci Signal. 2013 Jul 30;6(286):ra63. doi: 10.1126/scisignal.2004177.
In sarcoma, the activity of NF-κB (nuclear factor κB) reduces the abundance of the microRNA (miRNA) miR-29. The tumor suppressor A20 [also known as TNFAIP3 (tumor necrosis factor-α-induced protein 3)] inhibits an upstream activator of NF-κB and is often mutated in lymphomas. In a panel of human sarcoma cell lines, we found that the activation of NF-κB was increased and, although the abundance of A20 protein and mRNA was decreased, the gene encoding A20 was rarely mutated. The 3' untranslated region (UTR) of A20 mRNA has conserved binding sites for both of the miRNAs miR-29 and miR-125. Whereas the expression of miR-125 was increased in human sarcoma tissue, that of miR-29 was decreased in most samples. Overexpression of miR-125 decreased the abundance of A20 mRNA, whereas reconstituting miR-29 in sarcoma cell lines increased the abundance of A20 mRNA and protein. By interacting directly with the RNA binding protein HuR (human antigen R; also known as ELAVL1), miR-29 prevented HuR from binding to the A20 3'UTR and recruiting the RNA degradation complex RISC (RNA-induced silencing complex), suggesting that miR-29 can act as a decoy for HuR, thus protecting A20 transcripts. Decreased miR-29 and A20 abundance in sarcomas correlated with increased activity of NF-κB and decreased expression of genes associated with differentiation. Together, the findings reveal a unique role of miR-29 and suggest that its absence may contribute to sarcoma tumorigenesis.
在肉瘤中，NF-κB（核因子κB）的活性降低了 microRNA（miRNA）miR-29 的丰度。肿瘤抑制因子 A20[也称为 TNFAIP3（肿瘤坏死因子-α诱导蛋白 3）]抑制 NF-κB 的上游激活剂，并且经常在淋巴瘤中发生突变。在一组人类肉瘤细胞系中，我们发现 NF-κB 的激活增加了，尽管 A20 蛋白和 mRNA 的丰度降低，但 A20 基因很少发生突变。A20 mRNA 的 3'非翻译区（UTR）具有结合两种 miRNA miR-29 和 miR-125 的保守结合位点。尽管 miR-125 在人类肉瘤组织中的表达增加，但在大多数样本中 miR-29 的表达减少。miR-125 的过表达降低了 A20 mRNA 的丰度，而在肉瘤细胞系中重新构建 miR-29 则增加了 A20 mRNA 和蛋白的丰度。miR-29 通过与 RNA 结合蛋白 HuR（人抗原 R；也称为 ELAVL1）直接相互作用，防止 HuR 结合到 A20 3'UTR 并招募 RNA 降解复合物 RISC（RNA 诱导的沉默复合物），表明 miR-29 可以作为 HuR 的诱饵，从而保护 A20 转录物。肉瘤中 miR-29 和 A20 丰度的降低与 NF-κB 活性的增加和与分化相关的基因表达的降低相关。总之，这些发现揭示了 miR-29 的独特作用，并表明其缺失可能有助于肉瘤的肿瘤发生。
