miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling

J Biol Chem. 2010 Nov 19;285(47):36995-7004. doi: 10.1074/jbc.M110.133744. Epub 2010 Sep 7.


The emerging concept of generating cancer stem cells from epithelial-mesenchymal transition has attracted great interest; however, the factors and molecular mechanisms that govern this putative tumor-initiating process remain largely elusive. We report here that miR-200a not only regulates epithelial-mesenchymal transition but also stem-like transition in nasopharyngeal carcinoma cells. We first showed that stable knockdown of miR-200a promotes the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype. More importantly, it also induced several stem cell-like traits, including CD133(+) side population, sphere formation capacity, in vivo tumorigenicity in nude mice, and stem cell marker expression. Consistently, stable overexpression of miR-200a switched mesenchyme-like C666-1 cells to the epithelial state, accompanied by a significant reduction of stem-like cell features. Furthermore, in vitro differentiation of the C666-1 tumor sphere resulted in diminished stem-like cell population and miR-200a induction. To investigate the molecular mechanism, we demonstrated that miR-200a controls epithelial-mesenchymal transition by targeting ZEB2, although it regulates the stem-like transition differentially and specifically by β-catenin signaling. Our findings reveal for the first time the function of miR-200a in shifting nasopharyngeal carcinoma cell states via a reversible process coined as epithelial-mesenchymal to stem-like transition through differential and specific mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Differentiation
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial-Mesenchymal Transition*
  • Female
  • Flow Cytometry
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / physiology*
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box Binding Homeobox 2
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • Homeodomain Proteins
  • MIRN200 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • RNA, Small Interfering
  • Repressor Proteins
  • ZEB2 protein, human
  • ZEB2 protein, mouse
  • Zinc Finger E-box Binding Homeobox 2
  • beta Catenin