title: Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells' sensitivity to paclitaxel.
abstract: The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3' UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy.
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.|Centre for Biotechnology, University of Turku, Turku, Finland.|Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery, Finland.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Tambe
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.|Centre for Biotechnology, University of Turku, Turku, Finland.|Turku Doctoral Program of Molecular Medicine, University of Turku, Turku, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Pruikkonen
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.|Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Mäki-Jouppila
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Gynecological Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Bente Vilming
authors.initials: BV
authors.lastname: Elgaaen
authors.affiliation: Department of Clinical Science, University of Bergen and Department of Clinical Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Anne Hege
authors.initials: AH
authors.lastname: Straume
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Huhtinen
authors.affiliation: Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland.|Auria Biobank, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Cárpen
authors.affiliation: Department of Clinical Science, University of Bergen and Department of Clinical Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
authors.affiliation: Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.|Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Ben
authors.initials: B
authors.lastname: Davidson
authors.affiliation: Research Programs Unit, Genome-Scale Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Sampsa
authors.initials: S
authors.lastname: Hautaniemi
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.|Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Marko J
authors.initials: MJ
authors.lastname: Kallio
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020090:Chromosome Segregation; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D016032:Randomized Controlled Trials as Topic; D014162:Transfection
chemical_list: C577697:MAD2L1 protein, human; C555448:MIRN493 microRNA, human; D064246:Mad2 Proteins; D035683:MicroRNAs; D017239:Paclitaxel
keywords: Chromosome Section; Mad2; aneuploidy; miR-493-3p; spindle assembly checkpoint; taxane resistance