title: A Polycomb-mir200 loop regulates clinical outcome in bladder cancer.
abstract: Bladder cancer (BC) is a highly prevalent disease, ranking fifth in the most common cancers worldwide. Various miRNAs have recently emerged as potential prognostic biomarkers in cancer. The miR-200 family, which repressed the epithelial-to-mesenchymal transition (EMT), is repressed in multiple advanced cancers. However, its expression and function in BC is still poorly understood. Here we show that miR-200 family displays increased expression, probably due to the activation of specific oncogenic signaling pathways, and reduced promoter methylation, in BC compared to normal bladder samples. Furthermore, we show that the expression of these miRNAs is decreased in high grade and stage tumors, and the down-regulation is associated with patient's poor clinical outcome. Our data indicate that the miR-200 family plays distinct roles in Non-Muscle (NMIBC) and Muscle-Invasive BC (MIBC). In MIBC, miR-200 expression post transcriptionally regulates EMT-promoting transcription factors ZEB1 and ZEB2, whereas suppresses BMI1 expression in NMIBC. Interestingly, we show that increased EZH2 and/or BMI1 expression repress the expression of miR-200 family members. Collectively, these findings support a model of BC progression through a coordinated action between the Polycomb Repression Complex (PRC) members repressing the miR-200 expression, which ultimately favors invasive BC development. Since pharmacological inhibition of EZH2 in BC cell lines lead to increased miR-200 expression, our findings may support new therapeutic strategies for BC clinical management.
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Segovia
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Rubio
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: López-Calderón
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.
authors.forename: Claudio
authors.initials: C
authors.lastname: Díaz-García
authors.affiliation: Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.|Uro-oncology Section, Universitary Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Villacampa
authors.affiliation: Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.|Uro-oncology Section, Universitary Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.|Uro-oncology Section, Universitary Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Gómez-Rodriguez
authors.affiliation: Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.|Uro-oncology Section, Universitary Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Anatomic Pathology Service, Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Rodriguez-Peralto
authors.affiliation: Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.|Uro-oncology Section, Universitary Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: de la Rosa
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London WC1E 6BT, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain.|Universitary Hospital 12 de Octubre, Research Institute 12 de Octubre i+12, 28041 Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C069077:BMI1 protein, human; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1
keywords: Polycomb; bladder cancer; epigenetics; miRNA; recurrence