ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer
ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer
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DOI：
10.1093/jnci/dju149
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发表时间：
2014-07-01
影响因子：
10.3
通讯作者：
Henderson, Michelle J.
中科院分区：
文献类型：
--
作者：
Hedditch, Ellen L.;Gao, Bo;Henderson, Michelle J.
背景 ATP 结合盒 (ABC) 转运蛋白在癌症生物学和耐药性中发挥着多种作用，但它们与浆液性上皮性卵巢癌 (EOC) 结局的关系尚不清楚。方法通过实时定量聚合酶链反应、表达微阵列数据分析和分析，评估了两个独立的高级别浆液性 EOC 肿瘤队列中临床结局与 ABC 转运蛋白基因表达之间的关系。 免疫组织化学。在全基因组关联研究中测试了临床结果与 ABCA 转运蛋白基因单核苷酸多态性之间的关联。通过集落形成和迁移测定来确定短干扰RNA介导的基因抑制的影响。通过 Kaplan-Meier 分析和对数秩检验评估与生存的关联。所有统计检验都是双向的。结果观察到“A”亚家族的 ABC 转运蛋白与结果的关联，但与多种药物转运蛋白没有观察到。原发肿瘤中 ABCA1、ABCA6、ABCA8 和 ABCA9 的高水平表达与浆液性卵巢癌患者的生存率降低具有统计学显着相关性。 ABCA5 和 rs536009 的 C 等位基因水平低与总生存期较短相关（死亡风险比 = 1.50；95% 置信区间 [CI] = 1.26 至 1.79；P = 6.5e-6）。 ABCA1、ABCA5 以及 ABCA8 或 ABCA9 的组合表达模式与特别差的结果相关（ABCA1、ABCA5 和 ABCA9 基因表达不良组的平均总生存期 = 33.2 个月，95% CI = 26.4 至 40.1；而 ABCA 基因表达有利组的平均总生存期为 55.3 个月，95% CI = 49.8 至 60.8；P = .001)，与肿瘤无关 阶段或手术减灭状态。抑制胆固醇转运蛋白 ABCA1 可抑制体外卵巢癌细胞的生长和迁移，而他汀类药物治疗可减少卵巢癌细胞的迁移。结论 ABCA 转运蛋白的表达与浆液性卵巢癌的不良预后相关，表明脂质转运是 EOC 中潜在的重要过程。
Background ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.Methods The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided.Results Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] = 1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.Conclusions Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.