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

Research output: Contribution to journalArticle

187 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

Fingerprint

Gastropoda
Epithelial-Mesenchymal Transition
Carcinogenesis
Prostate
MicroRNAs
Prostatic Neoplasms
Adenocarcinoma
Prostatic Hyperplasia
Transforming Growth Factors
Phenotype
Bone and Bones

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., ... 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

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

In: Oncogene, Vol. 32, No. 3, 17.01.2013, p. 296-306.

Research output: Contribution to journalArticle

Liu, YN, Yin, JJ, Abou-Kheir, W, Hynes, PG, Casey, OM, Fang, L, Yi, M, Stephens, RM, 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, vol. 32, no. 3, pp. 296-306. https://doi.org/10.1038/onc.2012.58
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. / MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. In: Oncogene. 2013 ; Vol. 32, No. 3. pp. 296-306.
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