Department of Pathology, School of Dentistry, Chosun University, Gwangju, Republic of Korea.
Oncogene. 2013 Jul 11;32(28):3339-49. doi: 10.1038/onc.2012.354. Epub 2012 Aug 20.
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.
化疗药物耐药是癌症治疗中的一个重大临床问题，这种耐药性与多药外排转运蛋白的细胞表达有关。本研究旨在探讨 HOXC6 在调节化疗药物多药耐药（MDR）中的作用。与亲本细胞系相比，HOXC6 基因在耐药细胞中过表达。转染实验表明，HOXC6 激活了 MDR-1 启动子活性。我们检测了一系列 MDR-1 启动子缺失突变体，并确定了 HOXC6 反应的最小区域位于 MDR-1 启动子的 TAAT 基序（-2243 bp）。有趣的是，HOXC6 在亲本细胞系中的过表达导致 MDR-1 表达上调。使用小干扰 RNA 抑制 HOXC6 的表达导致 MDR-1 的抑制。我们确定在 MDR 细胞中敲低 HOXC6 表达可增加其对紫杉醇的敏感性。流式细胞术分析表明，siHOXC6 可诱导紫杉醇诱导的细胞凋亡，并且伴随着紫杉醇的蓄积增加和释放减少。综上所述，我们的研究结果表明，HOXC6 的表达是通过调节 MDR-1 导致化疗药物耐药的一个重要机制。
