Abstract
Paclitaxel is a first-line drug for treating epithelial ovarian cancer (EOC). However, prognosis for patients with advanced stage cancer remains poor due to primary or acquired drug resistance. Therefore, overcoming chemoresistance is one of the greatest challenges in treating EOC. In this study, we identified microRNAs (miRNA) that regulate paclitaxel resistance and tested their potential utility as therapeutic targets. Paclitaxel-resistant cell lines were established using two EOC cell lines: SKVO3ip1 and HeyA8. miRNA PCR arrays showed that miR-194-5p was downregulated in paclitaxel-resistant cells. Forced expression of miR-194-5p resensitized resistant cells to paclitaxel. Conversely, miR-194-5p inhibition induced paclitaxel resistance in parental cells. In silico analysis and luciferase reporter assay revealed that MDM2 is a direct target of miR-194-5p. MDM2 was upregulated in paclitaxel resistant cells compared with parental cells. MDM2 inhibition also resensitized resistant cells to paclitaxel and forced MDM2 induced paclitaxel resistance in parental cells. miR-194-5p induced p21 upregulation and G1 phase arrest in resistant cells by downregulating MDM2. Furthermore, a public database showed that high MDM2 expression was associated with a shorter progression-free survival in EOC patients treated with paclitaxel. Collectively, our results show that restoring miR-194-5p expression resensitizes EOCs to paclitaxel, and this may be exploited as a therapeutic option.
Highlights
Ovarian cancer is the most lethal gynecological malignancy and the fifth leading cause of cancer-related death in women in developed countries [1]
A public database showed that high MDM2 expression was associated with a shorter progression-free survival in epithelial ovarian cancer (EOC) patients treated with paclitaxel
MiR-194-5p is downregulated in paclitaxel-resistant ovarian cancer cell lines
Summary
Ovarian cancer is the most lethal gynecological malignancy and the fifth leading cause of cancer-related death in women in developed countries [1]. The majority of ovarian cancers are epithelial ovarian cancer (EOC) and the standard therapy for advanced EOC involves both cytoreductive surgery and intensive chemotherapy, with combination paclitaxel and platinum as the standard adjuvant chemotherapy regimen [2]. Despite these multimodal treatments, patients eventually face recurrence and the 5-year survival rate remains, at most, 30% and has not improved during the past 20 years [1]. The combination of taxane and platinum has remained the first-line chemotherapy for ovarian cancer treatment for the past 20 years [2, 3]. Considerable progress has been made toward understanding the mechanisms that underlie paclitaxel resistance; the molecular mechanisms underlying this resistance are still not completely elucidated. microRNAs (miRNAs) are endogenous non-coding RNAs approximately www.oncotarget.com
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
