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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.
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MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.

机译：MicroRNA 221和222通过试剂盒受体下调抑制正常的红细胞生成和红白血病细胞的生长。

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摘要

MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression primarily through translational repression. In erythropoietic (E) culture of cord blood CD34+ progenitor cells, the level of miR 221 and 222 is gradually and sharply down-modulated. Hypothetically, this decline could promote erythropoiesis by unblocking expression of key functional proteins. Indeed, (i) bioinformatic analysis suggested that miR 221 and 222 target the 3' UTR of kit mRNA; (ii) the luciferase assay confirmed that both miRs directly interact with the kit mRNA target site; and (iii) in E culture undergoing exponential cell growth, miR down-modulation is inversely related to increasing kit protein expression, whereas the kit mRNA level is relatively stable. Functional studies show that treatment of CD34+ progenitors with miR 221 and 222, via oligonucleotide transfection or lentiviral vector infection, causes impaired proliferation and accelerated differentiation of E cells, coupled with down-modulation of kit protein: this phenomenon, observed in E culture releasing endogenous kit ligand, is magnified in E culture supplemented with kit ligand. Furthermore, transplantation experiments in NOD-SCID mice reveal that miR 221 and 222 treatment of CD34+ cells impairs their engraftment capacity and stem cell activity. Finally, miR 221 and 222 gene transfer impairs proliferation of the kit+ TF-1 erythroleukemic cell line. Altogether, our studies indicate that the decline of miR 221 and 222 during exponential E growth unblocks kit protein production at mRNA level, thus leading to expansion of early erythroblasts. Furthermore, the results on kit+ erythroleukemic cells suggest a potential role of these miRs in cancer therapy.
机译：微小RNA（miR）是小的非编码RNA，主要通过翻译抑制来调节基因表达。在脐带血CD34 +祖细胞的促红细胞（E）培养中，miR 221和222的水平逐渐而急剧地下调。从理论上讲，这种下降可能会通过释放关键功能蛋白的表达来促进红细胞生成。实际上，（i）生物信息学分析表明miR 221和222靶向试剂盒mRNA的3'UTR； （ii）萤光素酶测定法证实两个miR都直接与试剂盒mRNA靶位点相互作用； （iii）在经历指数细胞生长的E培养物中，miR下调与试剂盒蛋白表达的增加呈负相关，而试剂盒mRNA水平则相对稳定。功能研究表明，通过寡核苷酸转染或慢病毒载体感染，用miR 221和222对CD34 +祖细胞进行处理，会导致E细胞的增殖和分化加快，以及试剂盒蛋白的下调：这种现象在E培养物中释放出内源性试剂盒配体在补充了试剂盒配体的E培养物中被放大。此外，在NOD-SCID小鼠中进行的移植实验表明，miR 221和222对CD34 +细胞的治疗会损害其植入能力和干细胞活性。最后，miR 221和222基因转移会损害kit + TF-1红白血病细胞系的增殖。总而言之，我们的研究表明，指数E生长期间miR 221和222的下降在mRNA水平上未阻断试剂盒蛋白的产生，从而导致了早期成红细胞的扩增。此外，关于kit +红白血病细胞的结果表明，这些miR在癌症治疗中具有潜在作用。

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