miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1
miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1
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miR-508-5p通过靶向ABCB1和ZNRD1调控胃癌多药耐药
DOI：
10.1038/onc.2013.297
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发表时间：
2014-06-19
期刊：
影响因子：
8
通讯作者：
Fan, D.
中科院分区：
文献类型：
--
作者：
Shang, Y.;Zhang, Z.;Fan, D.
多药耐药（MDR）通常与胃癌的不良预后相关。本研究通过高通量功能筛选共发现了11种调控胃癌MDR的microRNA（miRNA），其中miR-508- 5 p逆转MDR的效率最高。miR-508- 5 p的过表达足以在体外逆转癌细胞对多种化疗药物的耐药性，并在体内使肿瘤对化疗敏感。进一步研究发现，miR-508- 5 p可直接靶向ABCB 1和ZNRD 1的3′-非翻译区，在mRNA和蛋白水平抑制其表达。同时，ZNRD 1的抑制导致ABCB 1的减少。这些发现表明miR-508- 5 p/ZNRD 1/ABCB 1调控环在胃癌MDR中具有关键作用。此外，miR-508- 5 p可作为胃癌总生存期的预后因子。这些数据揭示了miR-508- 5 p在胃癌MDR调控中的重要作用，提示miR-508- 5 p在胃癌耐药预测和治疗中具有潜在的应用价值。
Multidrug resistance (MDR) is usually correlated with the poor prognosis of gastric cancer. In this study, we revealed a total of 11 microRNAs (miRNA) that regulated MDR of gastric cancer via high-throughput functional screening, and miR-508-5p reversed MDR most efficiently among these candidate miRNAs. The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3′-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1. These findings suggest that a miR-508-5p/ZNRD1/ABCB1 regulatory loop has a critical role in MDR in gastric cancer. In addition, miR-508-5p could be used as a prognostic factor for overall survival in gastric cancer. These data reveal an important role for miR-508-5p in the regulation of MDR in gastric cancer, and suggest the potential application of miR-508-5p in drug resistance prediction and treatment.