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Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR

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Title: Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR
Authors: Castellano, L
Dabrowska, A
Pellegrino, L
Ottaviani, S
Cathcart, P
Frampton, A
Krell, J
Stebbing, J
Item Type: Journal Article
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.
Issue Date: 25-Jan-2017
Date of Acceptance: 5-Jan-2017
URI: http://hdl.handle.net/10044/1/43817
DOI: https://dx.doi.org/10.1093/nar/gkx022
ISSN: 1362-4962
Publisher: Oxford University Press (OUP)
Start Page: 4401
End Page: 4412
Journal / Book Title: Nucleic Acids Research
Volume: 45
Issue: 8
Copyright Statement: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Sponsor/Funder: Action Against Cancer
Funder's Grant Number: 042016-06
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
MITOTIC CHECKPOINT PROTEIN
CANCER-CELLS
BREAST-CANCER
TUMOR SUPPRESSION
IN-VIVO
MICRORNA
GENES
CYTOKINESIS
MOTIFS
HYPERMETHYLATION
Developmental Biology
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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