論文 - 詳細
| RRC ID | 61799 |
|---|---|
| 著者 | Makii C, Oda K, Ikeda Y, Sone K, Hasegawa K, Uehara Y, Nishijima A, Asada K, Koso T, Fukuda T, Inaba K, Oki S, Machino H, Kojima M, Kashiyama T, Mori-Uchino M, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Fujiwara K, Aburatani H, Osuga Y, Fujii T. |
| タイトル | MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53. |
| ジャーナル | Oncotarget |
| Abstract |
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. |
| 巻・号 | 7(46) |
| ページ | 75328-75338 |
| 公開日 | 2016-11-15 |
| DOI | 10.18632/oncotarget.12175 |
| PII | 12175 |
| PMID | 27659536 |
| PMC | PMC5342744 |
| MeSH | Adenocarcinoma, Clear Cell / drug therapy Adenocarcinoma, Clear Cell / genetics* Adenocarcinoma, Clear Cell / metabolism Adenocarcinoma, Clear Cell / mortality Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects Apoptosis / genetics Cell Line, Tumor Cell Survival / genetics Disease Models, Animal Female Gene Expression Humans Hypoxia / drug therapy Hypoxia / genetics Hypoxia / metabolism Hypoxia-Inducible Factor 1, alpha Subunit / genetics Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Imidazolines / pharmacology Mice Molecular Targeted Therapy Neovascularization, Pathologic / genetics Neovascularization, Pathologic / metabolism Ovarian Neoplasms / drug therapy Ovarian Neoplasms / genetics* Ovarian Neoplasms / metabolism Ovarian Neoplasms / mortality Prognosis Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors* Proto-Oncogene Proteins c-mdm2 / genetics Proto-Oncogene Proteins c-mdm2 / metabolism Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism |
| IF | 5.168 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | JHOC-7(RCB1688) JHOC-9(RCB2226) |