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-

• 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

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使用培养的细胞系和手术标本阐明人卵巢癌细胞核YB-1与顺铂耐药之间的关系。研究方法：通过Western印迹分析检测顺铂敏感和耐药的人卵巢癌细胞系的细胞内YB-1定位。此外，35对手术标本来自同一患者的原发性和匹配的复发性卵巢癌的细胞核YB-1的表达进行了评估，免疫组化染色。结果如下：细胞核和细胞质提取物的Western印迹分析表明，顺铂耐药细胞显示出更高的核YB-1表达比敏感的亲本细胞。免疫组化分析显示，10对病例由原发灶核YB-1阴性转为复发灶核YB-1阳性，2对病例由阳性转为阴性。结论：YB-1在人乳腺癌细胞中的表达 ...更多信息 可能是一个有用的预测标志物，表明顺铂敏感性和/或靶分子，以治疗复发性卵巢癌的顺铂为基础的二线化疗。第二项研究的目的是通过肿瘤样品中ABC转运蛋白表达的相对mRNA水平来表征具有不利临床结果的患者，并检查每种ABC转运蛋白的相对mRNA水平是否可以是肿瘤细胞增殖的有用预测因子。晚期卵巢癌的无进展生存率。研究方法：我们采用实时荧光定量逆转录-聚合酶链反应（real-time reverse transcription-PCR）检测了30例原发性卵巢浆液性乳头状腺癌患者的肿瘤样本中MDR 1、MRP 1、MRP 2和MRP 3 mRNA的表达，并评估其与临床结局的相关性。所有30例患者根据减积手术和铂类化疗后的临床结局分为3组：8例患者被分为不利组; 11例被分为有利组; 11例被分为中间组。结果如下：3组间MRP 1和MRP 3的相对mRNA水平差异有统计学意义，多重比较显示，不利组MRP 1和MRP 3的mRNA水平明显高于有利组。MRP 1和MRP 3的相对mRNA表达水平显著相关。在30例浆液性乳头状腺癌患者中，单因素和多因素分析表明，MRP 1的相对高表达水平与短期无进展生存期显著相关。结论：在晚期卵巢浆液性腺癌患者中，这些结果表明，在其肿瘤样本中协调的MRP 1和MRP 3 mRNA表达水平的增加表征了预后不良的患者。此外，更高水平的MRP 1 mRNA表达可以作为预测较短无进展生存期的有用指标。少

项目成果

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