Downregulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression

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// 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; paclitaxel resistance; MDM2; ovarian cancer Received: September 14, 2018 Accepted: January 03, 2019 Published: January 18, 2019 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.