Oncotarget

Research Papers:

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

Koji Nakamura _, Kenjiro Sawada, Mayuko Miyamoto, Yasuto Kinose, Akihiko Yoshimura, Kyoso Ishida, Masaki Kobayashi, Aasa Shimizu, Erika Nakatsuka, Kae Hashimoto, Seiji Mabuchi and Tadashi Kimura

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Oncotarget. 2019; 10:673-683. https://doi.org/10.18632/oncotarget.26586

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Abstract

Koji Nakamura1,2, Kenjiro Sawada1, Mayuko Miyamoto1, Yasuto Kinose1,3, Akihiko Yoshimura1, Kyoso Ishida1, Masaki Kobayashi1, Aasa Shimizu1, Erika Nakatsuka1, Kae Hashimoto1, Seiji Mabuchi1 and Tadashi Kimura1

1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, 5650871, Japan

2Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA

3Penn 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.


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