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

Castellano, Leandro, Dabrowska, Aleksandra, Pellegrino, Loredana, Ottaviani, Silvia, Cathcart, Paul, Frampton, Adam E, Krell, Jonathan and Stebbing, Justin (2017) Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR. Nucleic Acids Research, 45 (8). pp. 4401-4412. ISSN 1362-4962

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Leandro Castellano
Date Deposited: 15 Jun 2018 08:50
Last Modified: 01 Jul 2019 15:17
URI: http://sro.sussex.ac.uk/id/eprint/76517

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