Hashimoto Tomoko, Yanaihara Nozomu, Okamoto Aikou, Nikaido Takashi, Saito Misato, Takakura Satoshi, Yasuda Makoto, Sasaki Hiroshi, Ochiai Kazunori, Tanaka Tadao
Department of Obstetrics and Gynecology, The Jikei University School of Medicine;
Exp Ther Med. 2011 Mar;2(2):213-219. doi: 10.3892/etm.2011.194. Epub 2011 Jan 18.
We previously reported that cyclin E (CCNE1) amplification is strongly associated with resistance to treatment in serous ovarian cancer by high-resolution oligonucleotide copy number analysis. Dysregulation of cell cycle control has been implicated as the key event in human oncogenesis, and aberrant expression of G1-S phase-related genes in particular has been reported in epithelial ovarian cancer (EOC). Nevertheless, there are conflicting results concerning the prognostic values of these abnormalities in EOC. This study focused on advanced serous EOC cases and investigated the association between the expression of G1-S phase-regulatory proteins and clinicopathological parameters. The utility of these proteins as prognostic factors was assessed, and whether these targets reflect chemoresistance of advanced serous EOC was investigated. A total of 66 patients treated by primary surgery were evaluated in this study. Immunohistochemical analysis for cyclin D1, pRb, p16, p53, p27(Kip1), p21(Waf1/Cip1) and cyclin E was performed on formalin-fixed tissue sections collected from primary surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including progression-free survival (PFS), overall survival (OS) and chemosensitivity, were examined. Upon univariate analysis, overexpression of cyclin D1 was positively correlated with reduced PFS (p=0.00062) and OS (p=0.00037). Reduced expression of p27(Kip1) was associated with shorter OS (p=0.064). Upon multivariate analysis, overexpression of cyclin D1 (p=0.0019), reduced expression of p27(Kip1) (p=0.042) and residual tumor volume (p=0.0092) were identified as independent predictors of OS. Overexpression of cyclin D1 (p=0.011) as well as residual tumor volume (p=0.006) were significantly associated with first-line chemosensitivity. In advanced serous EOC, overexpression of cyclin D1 contributed largely to poor prognosis, and this may have been in part mediated by chemoresistance. Cyclin D1 is a possible target for overcoming the refractory nature of advanced serous EOC.
我们之前报道过，通过高分辨率寡核苷酸拷贝数分析发现，细胞周期蛋白E（CCNE1）扩增与浆液性卵巢癌的治疗耐药性密切相关。细胞周期调控失调被认为是人类肿瘤发生的关键事件，尤其在上皮性卵巢癌（EOC）中，G1-S期相关基因的异常表达已有报道。然而，关于这些异常在EOC中的预后价值存在相互矛盾的结果。本研究聚焦于晚期浆液性EOC病例，调查了G1-S期调节蛋白表达与临床病理参数之间的关联。评估了这些蛋白作为预后因素的效用，并研究了这些靶点是否反映晚期浆液性EOC的化疗耐药性。本研究共评估了66例接受初次手术治疗的患者。对从初次手术标本中收集的福尔马林固定组织切片进行细胞周期蛋白D1、pRb、p16、p53、p27（Kip1）、p21（Waf1/Cip1）和细胞周期蛋白E的免疫组化分析。检查了这些蛋白的表达与临床病理参数之间的相关性，包括无进展生存期（PFS）、总生存期（OS）和化疗敏感性。单因素分析显示，细胞周期蛋白D1的过表达与PFS降低（p = 0.00062）和OS降低（p = 0.00037）呈正相关。p27（Kip1）表达降低与较短的OS相关（p = 0.064）。多因素分析确定，细胞周期蛋白D1的过表达（p = 0.0019）、p27（Kip1）表达降低（p = 0.042）和残余肿瘤体积（p = 0.0092）是OS的独立预测因素。细胞周期蛋白D1的过表达（p = 0.011）以及残余肿瘤体积（p = 0.006）与一线化疗敏感性显著相关。在晚期浆液性EOC中，细胞周期蛋白D1的过表达在很大程度上导致了不良预后，这可能部分是由化疗耐药介导的。细胞周期蛋白D1是克服晚期浆液性EOC难治性的一个可能靶点。
