miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes
miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes
复制标题
miR-181a/b 通过靶向多个抗凋亡基因显着增强慢性淋巴细胞白血病细胞的药物敏感性。
DOI：
10.1093/carcin/bgs179
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发表时间：
2012-07-01
期刊：
影响因子：
4.7
通讯作者：
Li, Jian-Yong
中科院分区：
文献类型：
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作者：
Zhu, Dan-Xia;Zhu, Wei;Li, Jian-Yong
MicroRNAs（miRNAs）在白血病的发生、发展过程中起着重要的调控作用。我们使用包含866个人类miRNA的平台，对6名中国慢性淋巴细胞白血病（CLL）患者和30名健康供体的外周B细胞进行了miRNA表达谱分析。在CLL细胞中最常见的miRNA变化包括miR-126、miR-572、miR-494、miR-923、miR-638、miR-130a、miR-181a和miR-181b的下调以及miR-29a、miR-660、miR-20a、miR-106b、miR-142 - 5p、miR-101、miR-30b、miR-34a、miR-let-7f、miR-20a、miR-106b、miR-142 - 5p、miR-101、miR-30b、miR-34a、miR-let-7f、miR-106a、miR-106b、miR-106a、miR-106b、miR-106a、miR-106b、miR-142 - 5p、miR-101、miR-30b、miR-34a、miR-17f、miR-1 miR-21和miR-155。在CLL细胞中下调的miRNAs中，我们发现miR-181 a/B表达水平在由未突变的免疫球蛋白重链可变状态和p53畸变定义的预后不良亚组中显著较低。此外，miR-181a和miR-181b的低表达与CLL患者的总生存期和无治疗生存期较短相关。我们进一步评估了在用miR-15a、miR-16 - 1、miR-34a、miR-181a和miR-181b模拟物转染来自40名患者的原代CLL细胞后氟达拉滨诱导的细胞凋亡。与miRNA对照相比，将miR-34a、miR-181a和miR-181b模拟物转染到来自p53野生型患者的CLL细胞中导致凋亡显著增加。然而，这些miRNA的强制表达对来自p53减毒患者的B-CLL细胞没有影响。我们进一步证明了miR-181a和miR-181b通过直接结合3'UTR抑制BCL-2、MCL-1和X连锁凋亡抑制蛋白。因此，这些结果表明，miR-181 a/B可能在CLL的发病机制中发挥重要作用，并可能提供一种可能的治疗途径和CLL中p53轴活性的敏感指标。
MicroRNAs (miRNAs) have been shown to play critical roles in regulating the progress of leukemia. We performed miRNA expression profile in six Chinese patients with chronic lymphocytic leukemia (CLL), and in peripheral B cells from pooled 30 healthy donors, using a platform containing 866 human miRNAs. The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Among the miRNAs down-regulated in CLL cells, we showed that miR-181a/b expression levels were significantly lower in poor prognostic subgroups defined by unmutated immunoglobulin heavy chain variable status and p53 aberrations. Furthermore, under-expression of miR-181a and miR-181b was associated with shorter overall survival and treatment-free survival in CLL patients. We further evaluated fludarabine-induced apoptosis after transfection of primary CLL cells from 40 patients with miR-15a, miR-16-1, miR-34a, miR-181a and miR-181b mimics. Transfection of miR-34a, miR-181a and miR-181b mimics into CLL cells from p53 wild-type patients led to significant increase in apoptosis compared with miRNA control. However, enforced expression of these miRNAs had no effect on B-CLL cells from p53-attenuated patients. We further demonstrated that miR-181a and miR-181b inhibiting BCL-2, MCL-1 and X-linked inhibitor of apoptosis protein by direct binding to 3'UTR. Thus, these results suggest that miR-181a/b may play important roles in the pathogenesis of CLL and may provide a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in CLL.