ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome
ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome
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DOI：
10.1158/1078-0432.ccr-06-0564
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发表时间：
2006-12-01
影响因子：
11.5
通讯作者：
Lage, Hermann
中科院分区：
文献类型：
--
作者：
Surowiak, Pawel;Materna, Verena;Lage, Hermann
目的：顺铂耐药是卵巢癌治疗的主要障碍。ABCC2通常定位于根尖细胞膜，可能导致顺铂耐药。在这里，我们发现ABCC2可以定位在包括卵巢癌细胞在内的各种人体组织的细胞质膜和核膜上。实验设计：采用41例国际妇产联合会III期卵巢癌顺铂治疗前标本和35例化疗后标本进行免疫组化检测ABCC2亚细胞水平。此外，还分析了11种卵巢癌细胞系以及由各种人体组织组成的组织微阵列。结果：ABCC2核膜定位与原发性一线化疗（P = 0.0013）和二次手术（P = 0.0060）的反应相关。复发患者在原发手术（P = 0.0003）和继发手术（P = 0.0024）时核膜表达较高。Kaplan-Meter分析显示，治疗前核膜ABCC2表达弱与总生存期（P = 0.04）和无进展生存期（P = 0.001）显著相关；化疗后，它与更长的无进展生存期显著相关（P = 0.038）。组织微阵列证实了ABCC2的核膜定位，特别是在低分化细胞中。在卵巢癌细胞中，它与对顺铂的耐药性相关，而在细胞质膜上的定位则不相关。结论：当ABCC2在核膜上表达时，在细胞培养系统和临床中赋予卵巢癌顺铂耐药性。因此，ABCC2定位可以预测铂治疗的结果。此外，ABCC2在人类组织核膜中的表达对包括干细胞在内的低分化细胞具有特异性。
Purpose: Cisplatin resistance is a major obstacle in the treatment of ovarian carcinoma. ABCC2 is commonly localized in apical cell membranes and could confer cisplatin resistance. Here, we show that ABCC2 can be localized in the cytoplasmic membrane as well as in the nuclear membrane of various human tissues including ovarian carcinoma cells.Experimental Design: For the subcellular detection of ABCC2, immunohistochemistry was done using 41 Federation Internationale des Gynaecologistes et Obstetristes stage III ovarian carcinoma specimens prepared before treatment with cisplatin-based schemes and 35 specimens from the same group after chemotherapy. Furthermore, 11 ovarian carcinoma cell lines as well as tissue microarrays consisting of various human tissues were analyzed.Results: Nuclear membranous localization of ABCC2 was associated with response to first-line chemotherapy at primary (P = 0.0013) and secondary surgery (P = 0.0060). Cases with relapse showed higher nuclear membrane expression at primary (P = 0.0003) and secondary surgery (P = 0.0024). Kaplan-Meter analyses showed that weak nuclear membrane ABCC2 expression before treatment was associated with significantly longer overall (P = 0.04) and progression-free survival (P = 0.001); following chemotherapy, it correlated with significantly longer progression-free survival (P = 0.038). Tissue microarrays confirmed nuclear membranous localization of ABCC2, in particular, in poorly differentiated cells. In ovarian carcinoma cells, it correlated with resistance against cisplatin, whereas localization in the cytoplasmic membrane did not.Conclusions: ABCC2 confers resistance to cisplatin of ovarian carcinoma in cell culture systems and in clinics when expressed in the nuclear membrane. Thus, ABCC2 localization can predict platinum therapy outcome. Furthermore, expression of ABCC2 in nuclear membranes in human tissues is specific for poorly differentiated cells including stem cells.