Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy
Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy
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DOI：
10.1158/1078-0432.ccr-03-0454
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发表时间：
2004-04-15
影响因子：
11.5
通讯作者：
Takebayashi, Y
中科院分区：
文献类型：
--
作者：
Nakayama, K;Kanzaki, A;Takebayashi, Y
目的：卵巢癌治疗的一个主要障碍是对顺铂化疗的内在/获得性耐药。据报道，铜转运 ATP 酶 (ATP7B) 与体外顺铂耐药性相关。然而，这种转运蛋白的临床意义此前尚未得到解决。我们的目的是研究ATP7B在卵巢癌中的表达及其与预后和顺铂治疗反应性降低是否相关。实验设计：我们回顾性研究了原发性卵巢癌中ATP7B和p53的表达及其与化疗效果的关系。通过手术切除 104 名接受顺铂化疗的卵巢癌患者的组织。我们使用针对 ATP7B 的单克隆抗体和针对 p53 蛋白的 DO7 抗体，对 104 例卵巢癌和邻近非肿瘤组织中的 ATP7B 和 p53 进行了免疫组织化学分析。 ATP7B和p53在卵巢癌患者预后中的重要性也在1988年至2001年间的死亡率随访数据的生存分析中得到检验。此外，在逆转录酶-PCR后使用单链构象多态性对六个Cu结合域和ATP结合域（可能对顺铂转运很重要）进行了突变分析。结果：肿瘤中ATP7B的细胞质染色程度不同在 34.6% 的分析癌症中（104 例中的 36 例）观察到细胞。在邻近的非肿瘤组织中未观察到 ATP7B 表达。低/中分化癌中ATP7B阳性率显着高于低度恶性潜能肿瘤/高分化癌（P = 0.0276）。与 ATP7B 阴性肿瘤患者相比，ATP7B 阳性肿瘤患者对化疗的反应明显较差（P = 0.025）。多变量 Cox 回归分析显示，ATP7B 表达（风险比，1.8；95% 置信区间，1.0-3.2，P = 0.048）以及国际妇产科医师联合会分期（风险比，2.0；95% 置信区间，1.1-3.6，P = 0.018）在调整p53 表达、分级和残留肿瘤。 31.5%（26/104 例）检测到 p53 表达。在表达 ATP7B 基因的人卵巢癌中，未观察到 6 个 Cu 结合域或 ATP 结合域发生突变。 结论：本研究表明，卵巢癌中 ATP7B 的过度表达与接受顺铂化疗的患者不良临床结果相关。因此，ATP7B表达可被认为是卵巢癌患者顺铂化疗耐药的预测标志物。我们进一步预测，靶向 ATP7B 的药物可能与基于顺铂的治疗方案联合使用，以改善卵巢癌患者的病情。
Purpose: A major obstacle in the treatment of ovarian carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Cu-transporting ATPase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate ATP7B expression in ovarian carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment.Experimental Design: We retrospectively examined the expression of ATP7B and p53 in primary ovarian carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 104 ovarian carcinomas patients who received cisplatin-based chemotherapy. We performed immunohistochemical analysis of ATP7B and p53 using a monoclonal antibody against ATP7B and DO7 antibody against p53 protein in 104 ovarian carcinomas and adjacent nonneoplastic tissues. The significance of ATP7B and p53 in the prognosis of patients with ovarian carcinomas was also examined in the survival analysis of mortality follow-up data covering the period between 1988 and 2001. Furthermore, mutation analysis at the six Cu-binding domain and ATP-binding domain, which may be important for cisplatin transport, were performed using single-strand conformational polymorphism after reverse transcriptase-PCR.Results: A variable degree of cytoplasmic staining of ATP7B in tumor cells was observed in 34.6% (36 of 104 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent nonneoplastic tissues. ATP7B positivity in poorly/moderately differentiated carcinoma was significantly higher than that in low malignant potential tumor/well-differentiated carcinoma (P = 0.0276). Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.025). The multivariate Cox regression analysis revealed that ATP7B expression (hazard ratio, 1.8; 95% confidence interval, 1.0-3.2, P = 0.048), as well as International Federation of Gynecologists and Obstetricians stage (hazard ratio, 2.0; 95% confidence interval, 1.1-3.6, P = 0.018), was prognostic for poor disease outcome after adjustment for p53 expression, grade, and residual tumor. p53 expression was detected in 31.5% (26/104 cases). No mutation was observed on the six Cu-binding domain or ATP-binding domain in human ovarian carcinomas expressing ATP7B gene.Conclusions: This study demonstrates that overexpression of ATP7B in ovarian carcinoma is correlated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B expression may be considered as a predictive marker of chemoresistance for cisplatin-based chemotherapy in patients with ovarian carcinoma. We further predict that drugs targeting ATP7B might be useful in combination with cisplatin-based regimen for the improvement of patients with ovarian carcinoma.