title: Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells.
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.
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Karolina
authors: K
authors: Weiner-Gorzel
authors: UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
authors: Eugene
authors: E
authors: Dempsey
authors: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors: Malgorzata
authors: M
authors: Milewska
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Aloysius
authors: A
authors: McGoldrick
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Valerie
authors: V
authors: Toh
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Aoibheann
authors: A
authors: Walsh
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Sinead
authors: S
authors: Lindsay
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Luke
authors: L
authors: Gubbins
authors: Molecular Department of Surgery, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors: Aoife
authors: A
authors: Cannon
authors: School of Pharmacy, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
authors: Daniel
authors: D
authors: Sharpe
authors: Molecular Department of Surgery, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors: Jacintha
authors: J
authors: O'Sullivan
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Madeline
authors: M
authors: Murphy
authors: Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
authors: Stephen F
authors: SF
authors: Madden
authors: Department of Surgery, Mater Misericordiae University Hospital, Dublin 7, Ireland.
authors: Malcolm
authors: M
authors: Kell
authors: UCD School of Medicine and Medical Science (SMMS), UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
authors: Amanda
authors: A
authors: McCann
authors: School of Pharmacy, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
authors: Fiona
authors: F
authors: Furlong
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics*; D019295:Computational Biology; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: C548883:MIRN433 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051361:Cyclin-Dependent Kinase 6; D017239:Paclitaxel
keywords: CDK6; chemoresistance; miR-433; ovarian cancer; senescence