Journal Article

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

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

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/384/331 / 631/80/84/2176 / 692/420/755 / 692/699/67/589/466 / Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Adenocarcinoma - physiopathology / Analysis / Angiogenesis / Animal models / Animals / Apoptosis / Benign / Bone growth / Carcinogenesis / Cell Biology / Cell differentiation / Cell Differentiation - drug effects / Cell Differentiation - genetics / Cell Line, Tumor / Development and progression / Differentiation / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / Feedback, Physiological - drug effects / Gene expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Expression Regulation, Neoplastic - genetics / Genetic aspects / Health aspects / Human Genetics / Humans / Hyperplasia / Internal Medicine / Male / Medicine / Medicine & Public Health / Mesenchymal Stem Cells - drug effects / Mesenchymal Stem Cells - pathology / Mesenchyme / Mice / MicroRNA / MicroRNAs - genetics / miRNA / Oncology / original-article / Phylogeny / Physiological aspects / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Prostatic Neoplasms - physiopathology / PTEN Phosphohydrolase - deficiency / Repressors / Signal transduction / Snail Family Transcription Factors / Transcription / Transcription Factors - metabolism / Transfer RNA / Transformation / Transforming Growth Factor beta - pharmacology / Tumor Suppressor Protein p53 - deficiency / Tumorigenesis