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.
Highlights
Worldwide ovarian cancer affects over 240,000 women annually
We previously demonstrated that transient overexpression of pre-miR-433 in A2780 cells decreased the apoptotic response of ovarian cancer cells to paclitaxel treatment [5]
We present data demonstrating a functional role of miR-433 in the induction of cellular senescence, thereby conferring resistance to paclitaxel in ovarian cancer cells
Summary
Worldwide ovarian cancer affects over 240,000 women annually. The most common subtype among ovarian cancer malignancies is high-grade serous ovarian cancer (HGSOC) which accounts for ~70% of all ovarian cancer presentations [1]. The 5-year survival rate for HGSOC ranges from 20% to 40% and is primarily dependent on the initial stage of diagnosis [2]. The standard management of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy consisting of a DNA-binding platinum agent (carboplatin) and a microtubule-stabilizing agent (paclitaxel). The rational given for such a high recurrence rate is predominantly associated with the “repopulation hypothesis” which assumes that recurrence depends on the ability of cancer cells to survive chemotherapy due to an intrinsic or acquired resistance [2]. Resistance to the microtubule-stabilizing agent, paclitaxel, can be associated with multiple mechanisms including an increased efflux of the drug, aberrant paclitaxel binding [4] or a disruption of the spindle assembly checkpoint (SAC) function [5]. Cell cycle arrest and subsequent cellular apoptosis is the predominant mechanism of action of these chemotherapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
