MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms

Oncogene. 2013 Jan 17;32(3):296-306. doi: 10.1038/onc.2012.58. Epub 2012 Feb 27.


Epithelial-mesenchymal transition (EMT) is a developmental program of signaling pathways that determine commitment to epithelial and mesenchymal phenotypes. In the prostate, EMT processes have been implicated in benign prostatic hyperplasia and prostate cancer progression. In a model of Pten- and TP53-null prostate adenocarcinoma that progresses via transforming growth factor β-induced EMT, mesenchymal transformation is characterized by plasticity, leading to various mesenchymal lineages and the production of bone. Here we show that SLUG is a major regulator of mesenchymal differentiation. As microRNAs (miRs) are pleiotropic regulators of differentiation and tumorigenesis, we evaluated miR expression associated with tumorigenesis and EMT. Mir-1 and miR-200 were reduced with progression of prostate adenocarcinoma, and we identify Slug as one of the phylogenetically conserved targets of these miRs. We demonstrate that SLUG is a direct repressor of miR-1 and miR-200 transcription. Thus, SLUG and miR-1/miR-200 act in a self-reinforcing regulatory loop, leading to amplification of EMT. Depletion of Slug inhibited EMT during tumorigenesis, whereas forced expression of miR-1 or miR-200 inhibited both EMT and tumorigenesis in human and mouse model systems. Various miR targets were analyzed, and our findings suggest that miR-1 has roles in regulating EMT and mesenchymal differentiation through Slug and functions in tumor-suppressive programs by regulating additional targets.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Adenocarcinoma / physiopathology
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics*
  • Feedback, Physiological / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / pathology
  • Mice
  • MicroRNAs / genetics*
  • PTEN Phosphohydrolase / deficiency
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Prostatic Neoplasms / physiopathology
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / pharmacology
  • Tumor Suppressor Protein p53 / deficiency


  • MIRN1 microRNA, human
  • MIRN200 microRNA, human
  • MicroRNAs
  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • PTEN Phosphohydrolase