title: Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR.
abstract: MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Dabrowska
authors.affiliation: Division of Cancer Therapeutic, The Institute of Cancer Research (ICR), Sutton, London SM2 5NG, UK.
authors.forename: Loredana
authors.initials: L
authors.lastname: Pellegrino
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ottaviani
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Cathcart
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krell
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), Hammersmith Hospital, London W12 0NN, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D048429:Cell Size; D043171:Chromosomal Instability; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D000097585:SS-B Antigen
chemical_list: D048948:14-3-3 Proteins; D001324:Autoantigens; D018797:Cell Cycle Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012261:Ribonucleoproteins; D044767:Ubiquitin-Protein Ligases; D000097585:SS-B Antigen; C528163:MIRN26 microRNA, human; C482983:YWHAE protein, human; C412002:CHFR protein, human