Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells

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Title: Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells
Authors: Weiner-Gorzel, KarolinaDempsey, EugeneMilewska, MalgorzataMcGoldrick, AloysiusToh, ValerieWalsh, AoibheannLindsay, SineadGubbins, LukeMurphy, MadelineMcCann, Amandaet al.
Permanent link: http://hdl.handle.net/10197/7252
Date: May-2015
Online since: 2015-12-02T11:25:45Z
Abstract: Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in β-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence.
Funding Details: Health Research Board
metadata.dc.description.othersponsorship: Mater Surgical Oncology Appeal
Type of material: Journal Article
Publisher: Wiley
Journal: Cancer medicine
Volume: 4
Issue: 5
Start page: 745
End page: 758
Copyright (published version): 2015 the Authors
Keywords: CDK6ChemoresistancemiR-433Ovarian cancerSenescence
DOI: 10.1002/cam4.409
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Biology & Environmental Science Research Collection
SBI Research Collection
Biomolecular and Biomedical Science Research Collection
Medicine Research Collection

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