iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe
iASPP and Chemoresistance in Ovarian Cancers: Effects on Paclitaxel-Mediated Mitotic Catastrophe
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DOI：
10.1158/1078-0432.ccr-11-0588
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发表时间：
2011-11-01
影响因子：
11.5
通讯作者：
Cheung, Annie N. Y.
中科院分区：
文献类型：
--
作者：
Jiang, LiLi;Siu, Michelle K. Y.;Cheung, Annie N. Y.
目的：iASPP是p53介导的细胞凋亡的特异性调节因子。在此，我们提供了第一个报告的表达谱的iASPP在卵巢上皮性肿瘤及其对紫杉醇chemosensitivity.Experimental设计：iASPP的表达和扩增状态进行了检查，在203个临床样本和17个细胞系，采用免疫组化，定量实时PCR和免疫印迹，并与临床病理参数。结果：iASPP蛋白和mRNA在卵巢癌组织和细胞株中的表达均显著增加，且与p53蛋白表达水平呈负相关。iASPP高表达与透明细胞癌亚型（P = 0.003）、卡铂和紫杉醇耐药（P = 0.04）、总体生存期较短（P 0.003）和无病生存期较短（P = 0.001）显著相关。多因素分析证实iASPP表达是独立的预后因素。iASPP mRNA表达的增加与基因扩增显着相关（P = 0.023）。iASPP在卵巢癌细胞中的过表达通过激活分离酶以p53非依赖性方式减少有丝分裂灾难而赋予紫杉醇抗性，而iASPP的敲除通过灭活分离酶而增强紫杉醇介导的有丝分裂灾难。securin和cyclinB 1/CDK 1复合物均参与iASPP对分离酶的调控。相反，过度表达的iASPP抑制细胞凋亡的p53依赖model.Conclusions：我们的数据显示关联的iASPP过度表达与基因扩增卵巢癌，并建议的作用，iASPP在不良的患者预后和化疗耐药性，通过阻断有丝分裂灾难。iASPP作为一种潜在的预后指标和化疗靶点值得进一步研究。临床癌症研究; 17（21）; 6924-33。（C）2011年《非洲标准化评论》。
Purpose: iASPP is a specific regulator of p53-mediated apoptosis. Herein, we provided the first report on the expression profile of iASPP in ovarian epithelial tumor and its effect on paclitaxel chemosensitivity.Experimental Design: Expression and amplification status of iASPP was examined in 203 clinical samples and 17 cell lines using immunohistochemistry, quantitative real-time PCR, and immunoblotting, and correlated with clinicopathologic parameters. Changes in proliferation, mitotic catastrophe, apoptosis, and underlying mechanism in ovarian cancer cells of different p53 status following paclitaxel exposure were also analyzed.Results: The protein and mRNA expression of iASPP was found to be significantly increased in ovarian cancer samples and cell lines. High iASPP expression was significantly associated with clear cell carcinoma subtype (P = 0.003), carboplatin and paclitaxel chemoresistance (P = 0.04), shorter overall (P 0.003), and disease-free (P = 0.001) survival. Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with gene amplification (P = 0.023). iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase, whereas knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1 complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode.Conclusions: Our data show an association of iASPP overexpression with gene amplification in ovarian cancer and suggest a role of iASPP in poor patient outcome and chemoresistance, through blocking mitotic catastrophe. iASPP should be explored further as a potential prognostic marker and target for chemotherapy. Clin Cancer Res; 17(21); 6924-33. (C)2011 AACR.