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miR-382-5p modulates the ATRA-induced differentiation of acute promyelocytic leukemia by targeting tumor suppressor PTEN
Cellular Signalling ( IF 4.8 ) Pub Date : 2018-11-17 , DOI: 10.1016/j.cellsig.2018.11.012
Dongdong Liu , Liang Zhong , Zhen Yuan , Juanjuan Yao , Pengqiang Zhong , Junmei Liu , Shifei Yao , Yi Zhao , Lu Liu , Min Chen , Lianwen Li , Beizhong Liu

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic differentiation and maturation. MicroRNAs play pivotal roles in formation of the leukemic phenotype. Previously, microRNA-382-5p (miR-382-5p) was upregulated in acute myeloid leukemia (AML) with t(15;17). In the present study, we found that miR-382-5p expression was elevated with ATRA-induced differentiation of APL. To investigate the potential functional role of miR-382-5p in APL differentiation, an APL cell line was transfected with miR-382-5p mimics, inhibitors, or negative control (NC). The results showed in APL cell line NB4 that miR-382-5p downregulation upon ATRA treatment was a key event in the drug response. Mechanistic investigations revealed that miR-382-5p targeted the ATRA-regulated tumor suppressor gene PTEN through direct binding to its 3′ UTR. Enforced expression of miR-382-5p or specific PTEN inhibitors inhibited ATRA-induced granulocytic differentiation via regulation of the cell cycle regulator cyclinD1. Conversely, PTEN overexpression promoted differentiation and enhanced sensitivity of NB4 cell line to physiological levels of ATRA. Finally, we found that PTEN overexpression restored PML nuclear bodies (NBs). Taken together, these results demonstrated that up-regulated miR-382-5p in NB4 cell line inhibited granulocytic differentiation through the miR-382-5p/PTEN axis, uncovering PTEN as a critical element in the granulocytic differentiation program induced by ATRA in APL.



中文翻译:

miR-382-5p通过靶向肿瘤抑制因子PTEN调节ATRA诱导的急性早幼粒细胞白血病的分化

在急性早幼粒细胞白血病(APL)中,全反式维甲酸(ATRA)治疗可诱导粒细胞分化和成熟。MicroRNA在白血病表型的形成中起关键作用。以前,在急性髓细胞性白血病(AML)中,t(15; 17)使microRNA-382-5p(miR-382-5p)上调。在本研究中,我们发现随着ATRA诱导的APL分化,miR-382-5p表达升高。为了研究miR-382-5p在APL分化中的潜在功能,将miR-382-5p模拟物,抑制剂或阴性对照(NC)转染了APL细胞系。结果显示在APL细胞系NB4中,ATRA治疗后miR-382-5p下调是药物反应中的关键事件。机理研究表明,miR-382-5p通过直接与其3'UTR结合而靶向ATRA调控的抑癌基因PTEN。miR-382-5p或特定PTEN抑制剂的强制表达抑制ATRA诱导的粒细胞分化通过调节细胞周期调节剂cyclinD1。相反,PTEN的过表达促进了NB4细胞系的分化并增强了其对ATRA生理水平的敏感性。最后,我们发现PTEN过表达恢复了PML核体(NBs)。综上,这些结果表明,NB4细胞系中的miR-382-5p上调通过miR-382-5p / PTEN轴抑制了粒细胞的分化,从而揭示了PTEN是APL在ATRA诱导的粒细胞分化程序中的关键元素。

更新日期:2018-11-17
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