The miR-223 host non-coding transcript linc-223 induces IRF4 expression in acute myeloid leukemia by acting as a competing endogenous RNA.
The miR-223 host non-coding transcript linc-223 induces IRF4 expression in acute myeloid leukemia by acting as a competing endogenous RNA.
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DOI：
10.18632/oncotarget.11165
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发表时间：
2016-09-13
期刊：
影响因子：
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通讯作者：
Fatica A
中科院分区：
文献类型：
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作者：
Mangiavacchi A;Sorci M;Masciarelli S;Larivera S;Legnini I;Iosue I;Bozzoni I;Fazi F;Fatica A
急性髓系白血病(AML)细胞的特征是终末髓系分化和异常增殖所需的遗传程序的改变。在这里，我们确定miR-223的宿主转录本Linc-223是AML中一个新的功能性长非编码RNA(LncRNA)。我们表明，从初级核转录本来看，miR-223和Linc-223的交替产物在单核细胞分化过程中受到精细调控。此外，Linc-223的表达抑制了AML细胞的细胞周期进程，促进了单核细胞的分化。我们还证明了内源性Linc-223定位于细胞质，并作为miR-125-5P的竞争内源RNA，miR-125-5P是白血病中的致癌microRNA。特别是，我们证明了Linc-223直接与miR-125-5p结合，并且它的击倒增加了miR-125-5p的抑制活性，导致其靶向干扰素调节因子4(IRF4)的下调，此前它被证明在体内抑制miR-125-5p的致癌活性。此外，来自原发AML样本的数据显示，Linc-223在不同AML亚型中显著下调。其中，这些发现表明，新发现的LncRNA Linc-223可能至少部分地通过与IRF4 mRNA的相互作用在髓系分化和白血病发生中发挥重要作用。
Alterations in genetic programs required for terminal myeloid differentiation and aberrant proliferation characterize acute myeloid leukemia (AML) cells. Here, we identify the host transcript of miR-223, linc-223, as a novel functional long non-coding RNA (lncRNA) in AML. We show that from the primary nuclear transcript, the alternative production of miR-223 and linc-223 is finely regulated during monocytic differentiation. Moreover, linc-223 expression inhibits cell cycle progression and promotes monocytic differentiation of AML cells. We also demonstrate that endogenous linc-223 localizes in the cytoplasm and acts as a competing endogenous RNA for miR-125-5p, an oncogenic microRNA in leukemia. In particular, we show that linc-223 directly binds to miR-125-5p and that its knockdown increases the repressing activity of miR-125-5p resulting in the downregulation of its target interferon regulatory factor 4 (IRF4), which it was previously shown to inhibit the oncogenic activity of miR-125-5p in vivo. Furthermore, data from primary AML samples show significant downregulation of linc-223 in different AML subtypes. Therein, these findings indicate that the newly identified lncRNA linc-223 may have an important role in myeloid differentiation and leukemogenesis, at least in part, by cross-talking with IRF4 mRNA.