MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms
| Autor: | Kathleen Kelly, Ming Yi, Yen-Nien Liu, Lei Fang, Heather Sheppard-Tillman, Victoria Seng, Philip Martin, Juan Juan Yin, Robert M. Stephens, Paul G. Hynes, Wassim Abou-Kheir, Orla Casey |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Epithelial-Mesenchymal Transition Slug Cellular differentiation Adenocarcinoma Molecular oncology Article Mice Growth factor receptor Transforming Growth Factor beta Cell Line Tumor Genetics Animals Humans PTEN Epithelial–mesenchymal transition Molecular Biology Feedback Physiological Regulation of gene expression biology PTEN Phosphohydrolase Prostatic Neoplasms Cell Differentiation Mesenchymal Stem Cells Transforming growth factor beta biology.organism_classification Gene Expression Regulation Neoplastic MicroRNAs embryonic structures Cancer research biology.protein Snail Family Transcription Factors Tumor Suppressor Protein p53 Transcription Factors |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2012.58 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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