title: miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions.
abstract: Recently, the inhibition of epithelial-mesenchymal-transition (EMT) by p53 has been described as a new mode of tumor suppression which presumably prevents metastasis. Here we report that activation of p53 down-regulates the EMT-inducing transcription factor SNAIL via induction of the miR-34a/b/c genes. Suppression of miR-34a/b/c caused up-regulation of SNAIL and cells displayed EMT markers and related features, as enhanced migration and invasion.  Ectopic miR-34a induced mesenchymal-epithelial-transition (MET) and down-regulation of SNAIL, which was mediated by a conserved miR-34a/b/c seed-matching sequence in the SNAIL 3'-UTR. miR-34a also down-regulated SLUG and ZEB1, as well as the stemness factors BMI1, CD44, CD133, OLFM4 and c-MYC. Conversely, the transcription factors SNAIL and ZEB1 bound to E-boxes in the miR-34a/b/c promoters, thereby repressing miR-34a and miR-34b/c expression. Since ectopic miR-34a prevented TGF-β-induced EMT, the repression of miR-34 genes by SNAIL and related factors is part of the EMT program. In conclusion, the frequent inactivation of p53 and/or miR-34a/b/c found in cancer may shift the equilibrium of these reciprocal regulations towards the mesenchymal state and thereby lock cells in a metastatic state.
authors: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: Helge
authors: H
authors: Siemens
authors: Rene
authors: R
authors: Jackstadt
authors: Sabine
authors: S
authors: Hünten
authors: Markus
authors: M
authors: Kaller
authors: Antje
authors: A
authors: Menssen
authors: Ursula
authors: U
authors: Götz
authors: Heiko
authors: H
authors: Hermeking
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D004591:Electrophoresis, Polyacrylamide Gel; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008156:Luciferases; D035683:MicroRNAs / Q000378:metabolism*; D018613:Microscopy, Confocal; D016685:Mitomycin; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D008156:Luciferases