MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53.
MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53.
复制标题
DOI：
10.18632/oncotarget.12175
复制
发表时间：
2016-11-15
期刊：
影响因子：
--
通讯作者：
Fujii T
中科院分区：
文献类型：
--
作者：
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
MDM2是一种泛素连接酶，通过蛋白酶体介导的降解抑制野生型TP53。我们评估了MDM2在卵巢透明细胞癌中的预后和治疗价值。采用芯片技术和实时荧光定量PCR技术分析MDM2在卵巢癌组织中的表达，采用Kaplan-Meier法和log-rank检验评价其与预后的关系。采用细胞活力测定、western blotting和流式细胞术检测MDM2 siRNA和MDM2抑制剂RG7112的抗肿瘤活性。通过小鼠异种移植瘤模型研究了RG7112的体内抗肿瘤作用。MDM2在透明细胞癌中的表达明显高于卵巢高级别浆液性癌（P = 0.0092）和正常组织（P = 0.035）。芯片检测的MDM2高表达与较差的无进展生存期和较差的总生存期显著相关（P = 0.0002, P = 0.0008）。值得注意的是，RG7112显著抑制了野生型TP53透明细胞癌细胞系的细胞活力。RG7112还强烈诱导细胞凋亡，增加TP53磷酸化，刺激促凋亡蛋白PUMA的表达。同样，siRNA敲低MDM2诱导细胞凋亡。最后，RG7112显著降低异种移植RMG-I透明细胞癌细胞的肿瘤体积（P = 0.033）和微血管密度（P = 0.011）。我们的研究结果强调了MDM2表达在透明细胞癌中的预后价值。因此，MDM2抑制剂如RG7112可能构成一类潜在的治疗药物。
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.
DOI：
10.18632/aging.100229
发表时间：
2010-11
期刊：
Aging
影响因子：
--
作者：
Lane DP;Verma C;Fang CC
通讯作者：
Fang CC