Cytopathologic study of intrinsic and acquired drug resistance of human ovarian cancer -the role of YB-1 and cMOAT/MRP2 gene-

人卵巢癌固有耐药和获得性耐药的细胞病理学研究-YB-1和cMOAT/MRP2基因的作用-

基本信息

批准号：
12671612
负责人：
HIRAKAWA Toshio
金额：
$ 1.66万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671612/
关键词：
Ovarian cancer Drug resistance YB-1 cMOAT1 MRP2 MRP1 MRP3 MRP-2 P糖蛋白 MRP-1 MRP-3

项目摘要

Purpose: The aim of the first study was to elucidate the association between nuclear YB-1 and cisplatin resistance in human ovarian cancer using cultured cell lines and surgical specimens. Methods: Intracellular YB-1 localization was examined by Western blot analysis for both cisplatin sensitive and resistant human ovarian cancer cell lines. Moreover, 35 pairs of surgical specimens derived from primary and matched recurrent ovarian cancers of the same patient were evaluated for their nuclear YB-1 expression by immunohistochemical staining. Results: Western blot analysis for nuclear and cytoplasmic extracts indicated that cisplatin-resistant cells showed much higher nuclear YB-1 expression than sensitive parental cells. Immunohistochemical analysis showed that 10 paired cases turned from negative nuclear YB-1 in primary lesions to positive nuclear YB-1 in recurrent lesions, whereas only two paired cases showed a reverse turn from positive to negative. Conclusion: The expression of YB-1 … More might be a useful predictive marker indicating cisplatin sensitivity and/or a target molecule to treat recurring ovarian cancers by cisplatin-based second-line chemotherapy.Purpose: The aim of the second study was to characterize patients with unfavorable clinical outcome by the relative mRNA levels of ABC transporter expression in their tumor samples and to examine whether relative mRNA levels of each of the ABC transporter can be a useful predictor of progression-free survival in advanced ovarian carcinoma. Methods: We examined tumor samples taken from 30 patients with primary serous papillary adenocarcinoma of the ovary for the expression of MDR1, MRP1, MRP2, and MRP3 mRNA using real-time reverse transcription-PCR, and we evaluated its correlation with clinical outcome. All 30 patients were divided into three groups according to clinical outcome after debulking surgery and platinum-based chemotherapy: 8 patients were classified into the unfavorable group; 11 were classified into the favorable group; and 11 were classified into intermediate group. Results: The relative mRNA levels of MRP1 and MRP3 were significantly different among the three groups, and the mRNA levels of MRP1 and MRP3 in the unfavorable group were significantly higher than those in the favorable group by multiple comparison. The relative mRNA levels of MRP1 expression were significantly correlated with those of MRP3 expression. In the 30 patients with serous papillary adenocarcinoma, univariate and multivariate analysis demonstrated that the high relative mRNA levels of MRP1 expression were significantly correlated with a short period of progression-free survival. Conclusion: In patients with advanced ovarian serous adenocarcinoma, these results suggest that increased levels of coordinated MRP1 and MRP3 mRNA expression in their tumor samples characterize patients with an unfavorable outcome. Furthermore, a higher level of MRP1 mRNA expression can be a candidate for a useful predictor of a shorter period of progression-free survival. Less

目的：第一项研究的目的是利用培养细胞系和手术标本阐明细胞核 YB-1 与顺铂耐药之间的关联。方法：通过蛋白质印迹分析检查顺铂敏感性的细胞内 YB-1 定位。此外，还评估了来自同一患者的 35 对原发性卵巢癌和相匹配的复发性卵巢癌的手术标本的核 YB-1。结果：细胞核和细胞质提取物的蛋白质印迹分析表明，顺铂耐药细胞的核 YB-1 表达比敏感的亲代细胞高得多。免疫组织化学分析显示，10 个配对病例的原代细胞核 YB-1 转为阴性。复发性病变中核 YB-1 的表达呈阳性，而只有两对病例显示从阳性到阴性的逆转。结论：YB-1 的表达可能是一个有用的预测标记。顺铂敏感性和/或通过基于顺铂的二线化疗治疗复发性卵巢癌的靶分子。目的：第二项研究的目的是通过肿瘤中 ABC 转运蛋白表达的相对 mRNA 水平来表征临床结果不良的患者方法：我们检查了取自 30 名原发性浆液性乳头状癌患者的肿瘤样本。采用实时逆转录PCR检测卵巢腺癌MDR1、MRP1、MRP2和MRP3 mRNA的表达，并评估其与临床结果的相关性。根据减瘤手术后的临床结果将所有30例患者分为三组。铂类化疗：不良组8例，良好组11例，中间组11例。三组间MRP1、MRP3差异显着，多重比较，不利组MRP1、MRP3 mRNA水平显着高于有利组，MRP1、MRP3相对mRNA表达量与MRP3相对mRNA水平显着相关。在 30 名浆液性乳头状腺癌患者中，单变量和多变量分析表明，MRP1 表达的高相对 mRNA 水平与短期无进展生存期显着相关。结论：在晚期卵巢浆液性腺癌患者中，这些结果表明，肿瘤样本中 MRP1 和 MRP3 mRNA 协调表达水平升高表明患者预后不良。此外，较高水平的 MRP1 mRNA 表达可能是有用的候选者。更短的无进展生存期的预测因子。