miR-146b-5p within BCR-ABL1-Positive Microvesicles Promotes Leukemic Transformation of Hematopoietic Cells
miR-146b-5p within BCR-ABL1-Positive Microvesicles Promotes Leukemic Transformation of Hematopoietic Cells
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BCR-ABL1 阳性微泡内的 miR-146b-5p 促进造血细胞白血病转化
DOI：
10.1158/0008-5472.can-15-2120
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发表时间：
2016
期刊：
影响因子：
11.2
通讯作者：
Guo An-Yuan
中科院分区：
文献类型：
--
作者：
Zhang Hong-Mei;Li Qing;Zhu Xiaojian;Liu Wei;Hu Hui;Liu Teng;Cheng Fanjun;You Yong;Zhong Zhaodong;Zou Ping;Li Qiubai;Chen Zhichao;Guo An-Yuan
越来越多的证据表明，细胞外微泡(MV)促进了癌症的进展和复发。利用K562慢性粒细胞白血病(CML)细胞来源的MVS将正常造血细胞转化为白血病样细胞的模型，通过转录因子(TF)和miRNAs的基因表达研究和网络分析，我们确定了这一过程的潜在机制。我们发现，在致癌转化的早期阶段，抗肿瘤的miRNAs增加，并启动了几条防御途径。后来，肿瘤抑制因子和参与细胞周期、DNA修复和能量代谢途径的基因上调。调控网络分析表明，许多转录因子和miRNAs负责该途径的失调和致癌转化。特别是，我们发现在MVS中高表达的miR-146b-5p协调了癌症相关基因的调节，促进了细胞转化过程。值得注意的是，用表达miR-146b-5p模拟物的K562细胞的MV处理受体细胞，发现它在很大程度上通过沉默肿瘤抑制NUMB而加速了转化过程。高水平的miR-146b-5p也增加了受体细胞的活性氧水平和基因组的不稳定性。综上所述，我们的发现表明，MVS中致癌miRNAs的上调如何促进造血细胞进入白血病状态，以及TF和miRNA共同调控分析在探索癌症的调节失调和发现关键因素方面的示范。癌症资源；76(10)；2901-11。
Evidence is accumulating that extracellular microvesicles (MV) facilitate progression and relapse in cancer. Using a model in which MVs derived from K562 chronic myelogenous leukemia (CML) cells transform normal hematopoietic transplants into leukemia-like cells, we defined the underlying mechanisms of this process through gene-expression studies and network analyses of transcription factors (TF) and miRNAs. We found that antitumor miRNAs were increased and several defense pathways were initiated during the early phases of oncogenic transformation. Later, oncomiRs and genes involved in cell cycle, DNA repair, and energy metabolism pathways were upregulated. Regulatory network analyses revealed that a number of TFs and miRNAs were responsible for the pathway dysregulation and the oncogenic transformation. In particular, we found that miR-146b-5p, which was highly expressed in MVs, coordinated the regulation of cancer-related genes to promote cell-transforming processes. Notably, treatment of recipient cells with MV derived from K562 cells expressing mimics of miR-146b-5p revealed that it accelerated the transformation process in large part by silencing the tumor-suppressorNUMB. High levels of miR-146b-5p also enhanced reactive oxygen species levels and genome instability of recipient cells. Taken together, our finding showed how upregulation of oncogenic miRNAs in MVs promote hematopoetic cells to a leukemic state, as well as a demonstration for TF and miRNA coregulatory analysis in exploring the dysregulation of cancers and discovering key factors.Cancer Res; 76(10); 2901–11. ©2016 AACR.