Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells
Genetic changes in the evolution of multidrug resistance for cultured human ovarian cancer cells
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DOI：
10.1002/gcc.20492
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发表时间：
2007-12-01
影响因子：
3.7
通讯作者：
Ling, Victor
中科院分区：
文献类型：
--
作者：
Buys, Timon P. H.;Chari, Raj;Ling, Victor
多重耐药 (MDR) 表型通常归因于 ATP 结合盒 (ABC) 转运蛋白（例如 P-糖蛋白 (ABCB1)）的活性。先前的研究表明，MDR 的调节可能不一定是单个基因特征。为了确定导致 MDR 出现的因素，我们对卵巢癌细胞系 SKOV3 和该细胞系的一系列 MDR 衍生物 (SKVCR) 进行了综合基因组学分析。随着耐药性的增加，基因表达的比较分析显示，除了 ABCB 1 之外，基因网络也显着激活。功能注释和通路分析表明，其中许多基因与细胞外基质相关，并且之前与肿瘤侵袭和细胞增殖有关。全基因组平铺路径阵列 CGH 的进一步研究表明，基因剂量的变化是激活其中几个过表达基因的关键。值得注意的是，SKVCR 系的全基因组图谱比对揭示了特定片段 DNA 改变的出现和衰退。最显着的改变是位于 16p I3 的新扩增子，其中包含 ABC 转运蛋白基因 ABCC1 和 ABCC6。在高度耐药的 SKVCR 系中，该扩增子的丢失与 7q2l.12 处出现了不同的扩增子同时出现，该扩增子包含 ABCB I。综合分析表明，在耐药性升级过程中，多个基因被激活，包括一系列 ABC 转运蛋白基因和可能与 ABCB 1 协同作用的基因。这些结果表明，MDR 表型的进化是癌细胞基因组中的动态、多基因过程。
The multidrug resistant (MDR) phenotype is often attributed to the activity of ATP-binding cassette (ABC) transporters such as P-glycoprotein (ABCB1). Previous work has suggested that modulation of MDR may not necessarily be a single gene trait. To identify factors that contribute to the emergence of MDR, we undertook integrative genomics analysis of the ovarian carcinoma cell line SKOV3 and a series of MDR derivatives of this line (SKVCRs). As resistance increased, comparative analysis of gene expression showed conspicuous activation of a network of genes in addition to ABCB 1. Functional annotation and pathway analysis revealed that many of these genes were associated with the extracellular matrix and had previously been implicated in tumor invasion and cell proliferation. Further investigation by whole genome tiling-path array CGH suggested that changes in gene dosage were key to the activation of several of these overexpressed genes. Remarkably, alignment of whole genome profiles for SKVCR lines revealed the emergence and decline of specific segmental DNA alterations. The most prominent alteration was a novel amplicon residing at 16p I3 that encompassed the ABC transporter genes ABCC1 and ABCC6. Loss of this amplicon in highly resistant SKVCR lines coincided with the emergence of a different amplicon at 7q2l.12, which harbors ABCB I. Integrative analysis suggests that multiple genes are activated during escalation of drug resistance, including a succession of ABC transporter genes and genes that may act synergistically with ABCB 1. These results suggest that evolution of the MDR phenotype is a dynamic, multi-genic process in the genomes of cancer cells.