Espadinha Anne-Sophie, Prouzet-Mauléon Valérie, Claverol Stéphane, Lagarde Valérie, Bonneu Marc, Mahon François-Xavier, Cardinaud Bruno
University of Bordeaux, INSERM U1035, Bordeaux, France.
University of Bordeaux, INSERM U1218, Bordeaux, France.
Oncotarget. 2017 Jul 12;8(44):76174-76188. doi: 10.18632/oncotarget.19192. eCollection 2017 Sep 29.
MicroRNAs (miRNAs) are regulators of several key patho-physiological processes, including cell cycle and apoptosis. Using microarray-based miRNA profiling in K562 cells, a model of chronic myeloid leukemia (CML), we found that the oncoprotein BCR-ABL1 regulates the expression of miR-21, an "onco-microRNA", found to be overexpressed in several cancers. This effect relies on the presence of two STAT binding sites on the promoter of miR-21, and on the phosphorylation status of STAT5, a transcription factor activated by the kinase activity of BCR-ABL1. Mir-21 regulates the expression of PDCD4 (programmed cell death protein 4), a tumor suppressor identified through a proteomics approach. The phosphoSTAT5 - miR-21 - PDCD4 pathway was active in CML primary CD34 cells, but also in acute myeloid leukemia (AML) models like MV4.11 and MOLM13, where the constitutively active tyrosine kinase FLT3-ITD plays a similar role to BCR-ABL1 in the K562 cell line.
微小RNA（miRNA）是包括细胞周期和细胞凋亡在内的多个关键病理生理过程的调节因子。利用基于微阵列的miRNA分析技术，对慢性粒细胞白血病（CML）模型K562细胞进行研究，我们发现癌蛋白BCR-ABL1可调节miR-21的表达，miR-21是一种“致癌微小RNA”，在多种癌症中均有过表达。这种效应依赖于miR-21启动子上两个STAT结合位点的存在，以及STAT5的磷酸化状态，STAT5是一种由BCR-ABL1激酶活性激活的转录因子。Mir-21可调节程序性细胞死亡蛋白4（PDCD4）的表达，PDCD4是通过蛋白质组学方法鉴定出的一种肿瘤抑制因子。磷酸化的STAT5 - miR-21 - PDCD4通路在CML原发性CD34细胞中具有活性，在急性髓系白血病（AML）模型如MV4.11和MOLM13中也具有活性，在这些模型中，组成型激活的酪氨酸激酶FLT3-ITD在K562细胞系中发挥着与BCR-ABL1类似的作用。
