Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Cancer Res. 2016 May 15;76(10):2901-11. doi: 10.1158/0008-5472.CAN-15-2120. Epub 2016 Mar 24.
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-suppressor NUMB 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.
越来越多的证据表明细胞外微囊泡（MV）促进癌症的进展和复发。使用 K562 慢性髓性白血病（CML）细胞衍生的 MV 使正常造血移植转化为白血病样细胞的模型，我们通过基因表达研究和转录因子（TF）和 miRNA 的网络分析定义了这个过程的潜在机制。我们发现，在致癌转化的早期阶段，抗肿瘤 miRNA 增加，并且启动了几种防御途径。后来，癌 miRNA 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 TF 和 miRNA 负责途径失调和致癌转化。特别是，我们发现高度表达于 MV 中的 miR-146b-5p 协调了癌症相关基因的调控，以促进细胞转化过程。值得注意的是，用表达 miR-146b-5p 模拟物的 K562 细胞衍生的 MV 处理受者细胞，发现它通过沉默肿瘤抑制因子 NUMB 来加速转化过程，NUMB 的高表达水平也增强了受者细胞的活性氧水平和基因组不稳定性。总之，我们的发现表明 MV 中致癌 miRNA 的上调如何促进造血细胞向白血病状态转化，以及 TF 和 miRNA 核心调控分析在探索癌症失调和发现关键因素方面的应用。Cancer Res; 76(10); 2901-11. ©2016 AACR.
