MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53
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Chinami Makii1, Katsutoshi Oda1, Yuji Ikeda1, Kenbun Sone1, Kosei Hasegawa2, Yuriko Uehara1,3, Akira Nishijima1,3, Kayo Asada1,3, Takahiro Koso1,3, Tomohiko Fukuda1, Kanako Inaba1, Shinya Oki1, Hidenori Machino1, Machiko Kojima1, Tomoko Kashiyama1, Mayuyo Mori-Uchino1, Takahide Arimoto1, Osamu Wada-Hiraike1, Kei Kawana1, Tetsu Yano4, Keiichi Fujiwara2, Hiroyuki Aburatani3, Yutaka Osuga1, Tomoyuki Fujii1
1Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
2Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
3Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
4Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan
Katsutoshi Oda, email: [email protected]
Keywords: MDM2, TP53, prognosis, molecular-targeted therapy, ovarian clear cell carcinoma
Received: May 14, 2016 Accepted: September 02, 2016 Published: September 21, 2016
MDM2, a ubiquitin ligase, suppresses wild type TP53 via proteasome-mediated degradation. We evaluated the prognostic and therapeutic value of MDM2 in ovarian clear cell carcinoma. MDM2 expression in ovarian cancer tissues was analyzed by microarray and real-time PCR, and its relationship with prognosis was evaluated by Kaplan-Meier method and log-rank test. The anti-tumor activities of MDM2 siRNA and the MDM2 inhibitor RG7112 were assessed by cell viability assay, western blotting, and flow cytometry. The anti-tumor effects of RG7112 in vivo were examined in a mouse xenograft model. MDM2 expression was significantly higher in clear cell carcinoma than in ovarian high-grade serous carcinoma (P = 0.0092) and normal tissues (P = 0.035). High MDM2 expression determined by microarray was significantly associated with poor progression-free survival and poor overall survival (P = 0.0002, and P = 0.0008, respectively). Notably, RG7112 significantly suppressed cell viability in clear cell carcinoma cell lines with wild type TP53. RG7112 also strongly induced apoptosis, increased TP53 phosphorylation, and stimulated expression of the proapoptotic protein PUMA. Similarly, siRNA knockdown of MDM2 induced apoptosis. Finally, RG7112 significantly reduced the tumor volume of xenografted RMG-I clear cell carcinoma cells (P = 0.033), and the density of microvessels (P = 0.011). Our results highlight the prognostic value of MDM2 expression in clear cell carcinoma. Thus, MDM2 inhibitors such as RG7112 may constitute a class of potential therapeutics.
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