Transcriptional regulation of MDR-1 by HOXC6 in multidrug-resistant cells
Transcriptional regulation of MDR-1 by HOXC6 in multidrug-resistant cells
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DOI：
10.1038/onc.2012.354
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发表时间：
2013-07-11
期刊：
影响因子：
8
通讯作者：
Ahn, S-G
中科院分区：
文献类型：
--
作者：
Kim, K-J;Moon, S-M;Ahn, S-G
对化疗药物的耐药性是癌症治疗中的一个重要的临床问题，并且这种耐药性与多药物外排转运蛋白的细胞表达有关。本研究的目的是探讨HOXC6在调节化疗药物多药耐药（MDR）中的作用。与亲代细胞系相比，HOXC6 基因在耐药细胞中被鉴定为过度表达。转染测定表明 HOXC6 激活 MDR-1 启动子活性。检查了一系列 MDR-1 启动子缺失突变体，并确定最小的 HOXC6 响应区位于 MDR-1 启动子的 TAAT 基序（-2243 bp）中。有趣的是，亲代细胞系中 HOXC6 的过度表达导致 MDR-1 表达上调。使用小干扰 RNA 抑制 HOXC6 导致 MDR-1 的抑制。我们确定敲低 MDR 细胞中 HOXC6 的表达会增加其对紫杉醇的敏感性。流式细胞术分析表明siHOXC6可以诱导紫杉醇诱导的细胞凋亡，并且伴随着紫杉醇积累的增加和释放的减少。综上所述，我们的研究结果表明 HOXC6 表达通过调节 MDR-1 是化疗耐药的重要机制。
Resistance to chemotherapeutic drugs is a significant clinical problem in the treatment of cancer and this resistance has been linked to the cellular expression of multidrug-efflux transporters. The aim of this study was to explore the role of HOXC6 in the regulation of multidrug resistance (MDR) to chemotherapeutic drugs. The HOXC6 gene was identified as being overexpressed in drug-resistant cells compared with parental cell lines. Transfection assays demonstrated that HOXC6 activated MDR-1 promoter activity. A series of MDR-1 promoter deletion mutants was examined and the minimal HOXC6-responsive region was identified to be in the TAAT motif (-2243 bp) of the MDR-1 promoter. Interestingly, overexpression of HOXC6 in the parental cell lines resulted in the upregulation of MDR-1 expression. The inhibition of HOXC6 using small interfering RNA led to the repression of MDR-1. We determined that knockdown of HOXC6 expression in MDR cells increased their sensitivity to paclitaxel. Flow cytometry analysis suggested that siHOXC6 could induce paclitaxel-induced apoptosis and that this was accompanied by an increased accumulation and a decreased release of paclitaxel. Taken together, our findings suggest that HOXC6 expression is an important mechanism of chemotherapeutic drug resistance via its regulation of MDR-1.