Downregulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression
2019
// Koji Nakamura 1, 2 , Kenjiro Sawada 1 , Mayuko Miyamoto 1 , Yasuto Kinose 1, 3 , Akihiko Yoshimura 1 , Kyoso Ishida 1 , Masaki Kobayashi 1 , Aasa Shimizu 1 , Erika Nakatsuka 1 , Kae Hashimoto 1 , Seiji Mabuchi 1 and Tadashi Kimura 1 1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, 5650871, Japan 2 Department of
Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA 3 Penn Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania Perelman School of Medicine, Biomedical Research Building II/III, Philadelphia, PA, 19104, USA Correspondence to: Kenjiro Sawada, email: daasawada@gyne.med.osaka-u.ac.jp Keywords: microRNA; miR-194-5p;
paclitaxelresistance;
MDM2; ovarian cancer Received: September 14, 2018 Accepted: January 03, 2019 Published: January 18, 2019 ABSTRACT
Paclitaxelis 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
paclitaxelresistance 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
paclitaxelresistance in parental cells. In silico analysis and luciferase reporter assay revealed that
MDM2is a direct target of miR-194-5p.
MDM2was upregulated in
paclitaxelresistant cells compared with parental cells.
MDM2inhibition also resensitized resistant cells to
paclitaxeland forced
MDM2induced
paclitaxelresistance 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
MDM2expression 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.
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