title: MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms.
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.
authors.affiliation: Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Y-N
authors.initials: YN
authors.lastname: Liu
authors.forename: J J
authors.initials: JJ
authors.lastname: Yin
authors.forename: W
authors.initials: W
authors.lastname: Abou-Kheir
authors.forename: P G
authors.initials: PG
authors.lastname: Hynes
authors.forename: O M
authors.initials: OM
authors.lastname: Casey
authors.forename: L
authors.initials: L
authors.lastname: Fang
authors.forename: M
authors.initials: M
authors.lastname: Yi
authors.forename: R M
authors.initials: RM
authors.lastname: Stephens
authors.forename: V
authors.initials: V
authors.lastname: Seng
authors.forename: H
authors.initials: H
authors.lastname: Sheppard-Tillman
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.forename: K
authors.initials: K
authors.lastname: Kelly
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D025461:Feedback, Physiological / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
chemical_list: C544547:MIRN1 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase