Abstract 505: Low miR-522 expression is correlated with paclitaxel resistance in ovarian cancer cells

Abstract

Abstract Background: Platinum-paclitaxel combination chemotherapy is standard postoperative treatment of ovarian cancer. Overcoming paclitaxel resistance is a critical issue in ovarian cancer treatment. Objectives: The aim of this study is to identify key miRNAs which regulate paclitaxel resistance and to pursue those potential as therapeutic targets. Methods: Using two serous ovarian cancer cell lines, SKVO3ip1 and HeyA8, paclitaxel resistant cell lines were established by a continuous exposure to paclitaxel. Taqman miRNA PCR array was performed and several miRNAs which were down-regulated in paclitaxel resistant cell lines were picked up. After the validation by miRNA PCR assay, miR-522 was found to be one of those. The clinical impact of miR-522 expression in ovarian cancer tissues was examined using a public database (PROGmiRV2). From a patient who had Stage IC clear cell carcinoma, RNA was extracted from formalin fixed paraffin-embedded (FFPE) tissue by laser microdissection. Thereafter, the miR-522 expression was compared with that from a normal contralateral ovary. Further, the miR-522 expression was analyzed among 4 ovarian cancer cell lines (RMG-1, RMG-2, HAC2 and KOC7C) and each IC50 value of paclitaxel was analyzed. The effect of miR-522 expression was assessed by transducing the precursor miRNA into paclitaxel resistant cells. Results: While the IC50 values of parental SKOV3ip1 and HeyA8 were 6.2 and 1.3 nM respectively, SKOV3ip1-PR and HeyA8-PR were 194.8 and 135.5 nM. MiRNA PCR array revealed 5 miRNAs including miR-522 were down-regulated in both paclitaxel resistant cell lines. Among those, the validation assay by miRNA PCR showed miR-522 was significantly down-regulated. In a public database analyzing 549 patients with serous adenocarcinomas, patients with the low expression of miR-522 had significantly correlated with worse relapse free survival than those with the high expression. In clinical paclitaxel resistant ovarian cancer tissue, the miR-522 expression was significantly down-regulated compared with that of a normal contralateral ovary. Each IC50 value of ovarian cancer cell lines (RMG-1, RMG-2, HAC2 and KOC7C) was 4.8, 222.1, 75.6, 66.9nM, respectively. Among those, IC50 values of 3 cell lines (RMG-2, HAC2 and KOC7C) were more than 50nM. In these cell lines, the expression level of miR-522 was significantly lower than that of paclitaxel sensitive SKOV3ip1. Transduction of miR-522 into paclitaxel resistant cells significantly sensitized to paclitaxel. Conclusion: MiR-522 is down-regulated in paclitaxel resistant cell lines and the low expression of miR-522 is correlated with shorter relapse free survival, indicating that the dysregulation of miR-522 is associated with the acquisition of paclitaxel resistance. The transduction of miR-522 into paclitaxel resistant cells sensitized these to paclitaxel. MiR-522 can be considered a therapeutic target to overcome paclitaxel resistance. Citation Format: Mayuko Miyamoto, Kenjiro Sawada, Akihiko Yoshimura, Erika Nakatsuka, Michiko Kodama, Kae Hashimoto, Seiji Mabuchi, Tadashi Kimura. Low miR-522 expression is correlated with paclitaxel resistance in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 505.