title: miR-146b-5p within BCR-ABL1-Positive Microvesicles Promotes Leukemic Transformation of Hematopoietic Cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Teng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Fanjun
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: You
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zou
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Qiubai
authors.initials: Q
authors.lastname: Li
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 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. guoay@hust.edu.cn.
authors.forename: An-Yuan
authors.initials: AY
authors.lastname: Guo
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D055252:Cell-Derived Microparticles / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D053263:Gene Regulatory Networks; D042822:Genomic Instability; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016044:Fusion Proteins, bcr-abl