title: MicroRNA let-7b regulates genomic balance by targeting Aurora B kinase.
abstract: The let-7 microRNA (miRNA) family has been implicated in the regulation of diverse cellular processes and disease pathogenesis. In cancer, loss-of-function of let-7 miRNAs has been linked to tumorigenesis via increased expression of target oncogenes. Excessive proliferation rate of tumor cells is often associated with deregulation of mitotic proteins. Here, we show that let-7b contributes to the maintenance of genomic balance via targeting Aurora B kinase, a key regulator of the spindle assembly checkpoint (SAC). Our results indicate that let-7b binds to Aurora B kinase 3'UTR reducing mRNA and protein expression of the kinase. In cells, excess let-7b induced mitotic defects characteristic to Aurora B perturbation including increased rate of polyploidy and multipolarity, and premature SAC inactivation that leads to forced exit from chemically induced mitotic arrest. Moreover, the frequency of aneuploid HCT-116 cells was significantly increased upon let-7b overexpression compared to controls. Interestingly, together with a chemical Aurora B inhibitor, let-7b had an additive effect on polyploidy induction in HeLa cells. In breast cancer patients, reduced let-7b expression was found to be associated with increased Aurora B expression in grade 3 tumors. Furthermore, let-7b was found downregulated in the most aggressive forms of breast cancer determined by clinicopathological parameters. Together, our findings suggest that let-7b contributes to the fidelity of cell division via regulation of Aurora B. Moreover, the loss of let-7b in aggressive tumors may drive tumorigenesis by up-regulation of Aurora B and other targets of the miRNA, which further supports the role of let-7b in tumor suppression.
authors: VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland; Centre for Biotechnology, University of Turku, 20520 Turku, Finland; Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery, Finland; Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20520 Turku, Finland.
authors: Jenni Heidi Eveliina
authors: JH
authors: Mäki-Jouppila
authors: VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland; Centre for Biotechnology, University of Turku, 20520 Turku, Finland; Turku Doctoral Program of Molecular Medicine, University of Turku, 20520 Finland; Department of Physiology, University of Turku, 20520 Turku, Finland.
authors: Sofia
authors: S
authors: Pruikkonen
authors: VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland; Centre for Biotechnology, University of Turku, 20520 Turku, Finland; Drug Research Doctoral Programme and FinPharma Doctoral Program Drug Discovery, Finland; Department of Physiology, University of Turku, 20520 Turku, Finland.
authors: Mahesh Balasaheb
authors: MB
authors: Tambe
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway.
authors: Miriam Ragle
authors: MR
authors: Aure
authors: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors: Tuuli
authors: T
authors: Halonen
authors: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors: Anna-Leena
authors: AL
authors: Salmela
authors: VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland; Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors: Leena
authors: L
authors: Laine
authors: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, 0424 Oslo, Norway.
authors: Anne-Lise
authors: AL
authors: Børresen-Dale
authors: VTT Health, VTT Technical Research Centre of Finland, 20520 Turku, Finland; Centre for Biotechnology, University of Turku, 20520 Turku, Finland. Electronic address: marko.kallio@btk.fi.
authors: Marko Johannes
authors: MJ
authors: Kallio
mesh_terms: D020413:3' Untranslated Regions; D064107:Aurora Kinase B / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011123:Polyploidy; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C487931:mirnlet7 microRNA, human; C576921:AURKB protein, human; D064107:Aurora Kinase B
keywords: Aneuploidy; Aurora B; Let-7b; MicroRNA; Mitosis