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.

译文

多药耐药 (MDR) 通常与胃癌的不良预后相关。在这项研究中,我们揭示了总共11个通过高通量功能筛选调节胃癌MDR的microrna (miRNA),并且在这些候选miRNA中miR-508-5p最有效地逆转MDR。miR-508-5p的过表达足以在体外逆转癌细胞对多种化学疗法的抗性,并在体内使肿瘤对化学疗法敏感。进一步的研究表明,miR-508-5p可以直接靶向ABCB1和含锌带结构域1 (ZNRD1) 的3 '-非翻译区,并在mRNA和蛋白质水平上抑制它们的表达。同时,ZNRD1的抑制导致abcb1的减少。这些发现表明,miR-508-5p/ZNRD1/ABCB1调节环在胃癌MDR中具有关键作用。此外,miR-508-5p可以用作胃癌总体生存的预后因素。这些数据揭示了miR-508-5p在胃癌MDR调控中的重要作用,并提示了miR-508-5p在耐药性预测和治疗中的潜在应用。

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