title: Selective repression of the oncogene cyclin D1 by the tumor suppressor miR-206 in cancers.
abstract: MicroRNAs (miRNAs) are deregulated in cancer and have been shown to exhibit both oncogenic and tumor suppressive functions. Although the functional effects of several miRNAs have been elucidated, those of many remain to be discovered. In silico analysis identified microRNA-206 (miR-206) binding sites in the 3'-untranslated regions (3'-UTR) of both the mouse and human CCND1 gene. Cyclin D1 is a recognized oncogene involved in direct phosphorylation of the retinoblastoma (Rb) protein and promoting cell cycle transition from G1 to S. miR-206 specifically binds to the CCND1 3'-UTR and mediates reduction of both cyclin D1 protein and mRNA. Expression of miR-206 induced a G1 arrest and a decrease in cell proliferation in breast cancer cells. Ectopic expression of miRNA-resistant cyclin D1 was able to reverse the miR-206-induced decrease in cell proliferation. Therefore, we identified miR-206 as an activator of cell cycle arrest resulting in a decrease in cell proliferation that is dependent on the inhibition of cyclin D1. Interestingly, prostatic cancer (PCa) cells express low levels of miR-206 resulting in deregulated cyclin D1 expression compared with non-transformed primary prostatic epithelial cells (PrEC). Finally, we demonstrate that cyclin D1 is regulated by miR-206 in PrEC but not in PCa cells and this is due to the absence of a CCND1 3'-UTR in these cells. This suggests that miR-206-based anti-cyclin D1 targeted therapy would be beneficial in cancers where cyclin D1 is overexpressed and contains a 3'-UTR.
authors.affiliation: Orbsen Therapeutics Ltd, Galway, Ireland.
authors.forename: S J
authors.initials: SJ
authors.lastname: Elliman
authors.affiliation: National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland.
authors.forename: B V
authors.initials: BV
authors.lastname: Howley
authors.affiliation: Biogen Idec, Inc., Cambridge, MA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Mehta
authors.affiliation: Pharmacology and Therapeutics, National University of Ireland Galway, Galway, Ireland.
authors.forename: H O
authors.initials: HO
authors.lastname: Fearnhead
authors.affiliation: Emerald Bio, Boston, MA, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Kemp
authors.affiliation: National Centre for Biomedical Engineering Science, National University of Ireland Galway, Galway, Ireland.
authors.forename: L R
authors.initials: LR
authors.lastname: Barkley
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