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

Y. N. Liu, J. J. Yin, W. Abou-Kheir, P. G. Hynes, O. M. Casey, L. Fang, M. Yi, R. M. Stephens, V. Seng, H. Sheppard-Tillman, P. Martin, K. Kelly

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197 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)296-306
Number of pages11
JournalOncogene
Volume32
Issue number3
DOIs
Publication statusPublished - Jan 17 2013
Externally publishedYes

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Keywords

  • EMT
  • miR-1
  • miR-200
  • prostate cancer
  • SLUG

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Liu, Y. N., Yin, J. J., Abou-Kheir, W., Hynes, P. G., Casey, O. M., Fang, L., Yi, M., Stephens, R. M., Seng, V., Sheppard-Tillman, H., Martin, P., & Kelly, K. (2013). MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene, 32(3), 296-306. https://doi.org/10.1038/onc.2012.58