Open AccessMDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53
Author(s) -
Chinami Makii,
Katsutoshi Oda,
Yuji Ikeda,
Kenbun Sone,
Kosei Hasegawa,
Yuriko Uehara,
Akira Nishijima,
Kenichi Asada,
Takahiro Koso,
Tomohiko Fukuda,
Kanako Inaba,
Sadaaki Oki,
Hidenori Machino,
Masahiro Kojima,
Tomoko Kashiyama,
Mayuyo MoriUchino,
Takahide Arimoto,
Osamu WadaHiraike,
Kei Kawana,
Tetsu Yano,
Keiichi Fujiwara,
Hiroyuki Aburatani,
Yutaka Osuga,
Tomoyuki Fujii
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.12175
Subject(s) - medicine , oncology , ovarian carcinoma , ovarian cancer , cancer research , mdm2 , gynecology , cancer , biology , cell culture , genetics
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.