title: TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops.
abstract: The process of epithelial-to-mesenchymal transition (EMT) is an essential type of cellular plasticity associated with a change from epithelial cells that function as a barrier consisting of a sheet of tightly connected cells to cells with properties of mesenchyme that are not attached to their neighbors and are highly motile. This phenotypic change occurs during development and also contributes to pathological processes, such as cancer progression. The molecular mechanisms controlling the switch between the fully epithelial and fully mesenchymal phenotypes and cells that have characteristics of both (partial EMT) are controversial, and multiple theoretical models have been proposed. To test these theoretical models, we systematically measured the changes in the abundance of proteins, mRNAs, and microRNAs (miRNAs) that represent the core regulators of EMT induced by transforming growth factor-β1 (TGF-β1) in the human breast epithelial cell line MCF10A at the population and single-cell levels. We provide experimental confirmation for a model of cascading switches in phenotypes associated with TGF-β1-induced EMT of MCF10A cells that involves two double-negative feedback loops: one between the transcription factor SNAIL1 and the miR-34 family and another between the transcription factor ZEB1 and the miR-200 family. Furthermore, our data showed that whereas the transition from epithelial to partial EMT was reversible for MCF10A cells, the transition from partial EMT to mesenchymal was mostly irreversible at high concentrations of TGF-β1.
authors.affiliation: Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China. Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Tian
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, 20 Dong-Da Street, Fengtai District, Beijing 100071, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China.
authors.forename: Ruoyan
authors.initials: R
authors.lastname: Li
authors.affiliation: Biodynamic Optical Imaging Center, Peking University, Beijing 100871, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA. jxing@vt.edu kumarans@vt.edu.
authors.forename: Subbiah
authors.initials: S
authors.lastname: Elankumaran
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA. Beijing Computational Science Research Center, Beijing 100084, China. jxing@vt.edu kumarans@vt.edu.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xing
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1