State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Gynecological Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Cancer Lett. 2018 Jul 28;427:9-17. doi: 10.1016/j.canlet.2018.04.013. Epub 2018 Apr 13.
Multiple Drug Resistance (MDR) of ovarian cancer is a severe trouble for clinical treatment and always contributes to a bad prognosis. AT-rich interaction domain 1 A (ARID1A) has been recognized as a bona fide tumor suppressor gene in recent years, with the highest mutation rate in ovarian cancer. Previous study illustrated that ARID1A expression is negatively correlated with chemoresistance of ovarian cancer cases. However, the specific role of ARID1A in chemoresistance of ovarian cancer remains elusive. In this study, we showed that ARID1A knockdown in ovarian cancer cells significantly reduced their apoptosis rate and led to MDR, while ectopic expression of ARID1A showed opposite effects. ARID1A depletion transcriptionally activates the expression of multidrug resistance-associated protein 2 (MRP2) following chromatin remodeling. Furthermore, IHC analysis of ovarian cancer samples confirmed that ARID1A expression was strong negatively correlated with MRP2 expression. Both ARID1A and MRP2 expression levels are correlated with sensitivity to platinum. Collectively, our results illustrated that ARID1A loss in ovarian cancer leads to MDR through upregulation of MRP2, providing an opportunity to overcome the ARID1A loss induced chemoresistance of ovarian cancer by targeting MRP2.
卵巢癌的多药耐药性（MDR）是临床治疗的严重难题，往往导致预后不良。富含 AT 的相互作用结构域 1A（ARID1A）近年来被认为是一种真正的肿瘤抑制基因，在卵巢癌中突变率最高。先前的研究表明，ARID1A 的表达与卵巢癌病例的化疗耐药性呈负相关。然而，ARID1A 在卵巢癌化疗耐药性中的具体作用仍不清楚。在这项研究中，我们表明，卵巢癌细胞中 ARID1A 的敲低显著降低了它们的细胞凋亡率并导致多药耐药性，而 ARID1A 的异位表达则显示出相反的效果。ARID1A 耗竭通过染色质重塑转录激活多药耐药相关蛋白 2（MRP2）的表达。此外，对卵巢癌样本的免疫组织化学分析证实，ARID1A 的表达与 MRP2 的表达呈强烈负相关。ARID1A 和 MRP2 的表达水平均与铂类药物敏感性相关。综上所述，我们的研究结果表明，ARID1A 在卵巢癌中的缺失通过上调 MRP2 导致多药耐药性，为通过靶向 MRP2 克服由 ARID1A 缺失引起的卵巢癌化疗耐药性提供了机会。
