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

Oncogene volume 32, pages 296–306 (2013)Cite this article

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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.

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Acknowledgements

We acknowledge the support of the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA. We thank Dr Chi-Ping Day, Dr Yvona Ward and Ross Lake for assistance.

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Author notes

  1. P Martin

    Present address: Current address: Center for Advanced Preclinical Research, SAIC-NCI, Frederick, MD, USA,

Authors and Affiliations

  1. Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

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

  2. Advanced Biomedical Computing Center, NCI-FCRDC, Frederick, MD, USA

    M Yi & R M Stephens

  3. These two authors contributed equally to this,

    Y-N Liu & J J Yin

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  1. Y-N Liu
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Correspondence to K Kelly.

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Liu, YN., Yin, J., Abou-Kheir, W. et al. MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene 32, 296–306 (2013). https://doi.org/10.1038/onc.2012.58

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