miR-150 exerts antileukemia activity in vitro and in vivo through regulating genes in multiple pathways.
miR-150 exerts antileukemia activity in vitro and in vivo through regulating genes in multiple pathways.
复制标题
DOI：
10.1038/cddis.2016.256
复制
发表时间：
2016-09-22
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
MicroRNAs是一类小的非编码RNA，在几乎所有重要的生物过程中都参与调控基因的表达。虽然越来越多的证据表明miR-150是一种重要的造血调控因子，但在各种类型的血液系统恶性肿瘤中，miR-150的调控被解除，但miR-150的确切作用机制在很大程度上尚不清楚。在这项研究中，我们发现miR-150在急性淋巴细胞白血病、急性髓系白血病和慢性髓系白血病患者的样本中下调，并在患者完全缓解后恢复正常。在异种移植白血病小鼠模型中，miR-150的修复显著抑制了白血病细胞的生长并诱导了细胞的凋亡，并降低了肿瘤的致瘤性。基因芯片分析确定了miR-150的多个新靶点，并通过实时定量聚合酶链式反应和荧光素酶报告基因分析进行了验证。基因本体论和途径分析说明了这些靶标在小分子代谢、转录调控、RNA代谢、癌症蛋白多糖合成、mTOR信号通路或Wnt信号通路中的潜在作用。有趣的是，敲除四个miR-150靶点中的一个(EIF4B、FOXO4B、PRKCA和TET3)显示出与miR-150修复相似的抗白血病活性。总之，我们的研究表明miR-150在人类白血病中通过多种机制发挥肿瘤抑制作用，并为将miR-150用作白血病治疗的新型治疗剂提供了理论基础。
MicroRNAs, a class of small noncoding RNAs, have been implicated to regulate gene expression in virtually all important biological processes. Although accumulating evidence demonstrates that miR-150, an important regulator in hematopoiesis, is deregulated in various types of hematopoietic malignancies, the precise mechanisms of miR-150 action are largely unknown. In this study, we found that miR-150 is downregulated in samples from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia, and normalized after patients achieved complete remission. Restoration of miR-150 markedly inhibited growth and induced apoptosis of leukemia cells, and reduced tumorigenicity in a xenograft leukemia murine model. Microarray analysis identified multiple novel targets of miR-150, which were validated by quantitative real-time PCR and luciferase reporter assay. Gene ontology and pathway analysis illustrated potential roles of these targets in small-molecule metabolism, transcriptional regulation, RNA metabolism, proteoglycan synthesis in cancer, mTOR signaling pathway, or Wnt signaling pathway. Interestingly, knockdown one of four miR-150 targets (EIF4B, FOXO4B, PRKCA, and TET3) showed an antileukemia activity similar to that of miR-150 restoration. Collectively, our study demonstrates that miR-150 functions as a tumor suppressor through multiple mechanisms in human leukemia and provides a rationale for utilizing miR-150 as a novel therapeutic agent for leukemia treatment.
登录
查看更多内容
影响因子：
12.3
作者：
Monticelli, Silvia;Ansel, K Mark;Xiao, Changchun;Socci, Nicholas D;Krichevsky, Anna M;Thai, To-Ha;Rajewsky, Nikolaus;Marks, Debora S;Sander, Chris;Rajewsky, Klaus;Rao, Anjana;Kosik, Kenneth S
通讯作者：
Kosik, Kenneth S
影响因子：
2.6
作者：
Kamezaki, Kenjiro;Luchsinger, Larry L.;Snoeck, Hans-Willem
通讯作者：
Snoeck, Hans-Willem
影响因子：
11.4
作者：
通讯作者：
--
DOI：
10.1073/pnas.0800121105
发表时间：
2008-04-01
影响因子：
11.1
作者：
Calin, George A.;Cimmino, Amelia;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
影响因子：
11.4
作者：
Badger-Brown, K. M.;Gillis, L. C.;Barber, D. L.
通讯作者：
Barber, D. L.