Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT-YB1-MDR1 Signaling Pathway
Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT-YB1-MDR1 Signaling Pathway
复制标题
人解旋酶 RECQL4 通过激活 AKT-YB1-MDR1 信号通路驱动胃癌顺铂耐药
DOI：
10.1158/0008-5472.can-15-2361
复制
发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Zhao, Yongliang
中科院分区：
文献类型：
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作者：
Mo, Dongliang;Fang, Hongbo;Zhao, Yongliang
参与各种DNA修复途径的DNA解旋酶RECQL 4的升高已被认为有助于各种人类癌症（包括胃癌）的致病性。在这项研究中，我们讨论了RECQL 4在人类胃癌中的预后和化疗意义，这还有待确定。我们观察到相对于正常胃组织，在所检查的三组独立的人胃癌样本中，RECQL 4 mRNA或蛋白质在>70%中显著增加。引人注目的是，原发性肿瘤中RECQL 4的高表达与较差的存活率密切相关，并且具有高RECQL 4表达的胃癌细胞系显示出对顺铂治疗的耐药性增加。机制研究揭示了RECQL 4在多药耐药基因MDR 1的转录调控中的新作用，通过与转录因子YB 1的物理相互作用。值得注意的是，在内源性RECQL 4水平较低的顺铂敏感性胃癌细胞中，RECQL 4的异位表达足以使其对顺铂产生耐药性，其方式与YB 1升高和MDR 1活化相关。相反，在具有高内源性RECQL 4的顺铂耐药胃癌细胞中，RECQL 4沉默抑制了YB 1磷酸化，降低了MDR 1表达，并使细胞对顺铂重新敏感。在建立RECQL 4作为胃癌细胞顺铂耐药的关键介质中，我们的研究结果提供了靶向RECQL 4或下游AKT-YB 1-MDR 1轴以改善胃癌治疗的治疗原理。(C)2016年AACR。
Elevation of the DNA-unwinding helicase RECQL4, which participates in various DNA repair pathways, has been suggested to contribute to the pathogenicity of various human cancers, including gastric cancer. In this study, we addressed the prognostic and chemotherapeutic significance of RECQL4 in human gastric cancer, which has yet to be determined. We observed significant increases in RECQL4 mRNA or protein in >70% of three independent sets of human gastric cancer specimens examined, relative to normal gastric tissues. Strikingly, high RECQL4 expression in primary tumors correlated well with poor survival and gastric cancer lines with high RECQL4 expression displayed increased resistance to cisplatin treatment. Mechanistic investigations revealed a novel role for RECQL4 in transcriptional regulation of the multidrug resistance gene MDR1, through a physical interaction with the transcription factor YB1. Notably, ectopic expression of RECQL4 in cisplatin-sensitive gastric cancer cells with low endogenous RECQL4 was sufficient to render them resistant to cisplatin, in a manner associated with YB1 elevation and MDR1 activation. Conversely, RECQL4 silencing in cisplatin-resistant gastric cancer cells with high endogenous RECQL4 suppressed YB1 phosphorylation, reduced MDR1 expression, and resensitized cells to cisplatin. In establishing RECQL4 as a critical mediator of cisplatin resistance in gastric cancer cells, our findings provide a therapeutic rationale to target RECQL4 or the downstream AKT-YB1-MDR1 axis to improve gastric cancer treatment. (C) 2016 AACR.