The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer.
The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer.
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miR27b-CCNG1-P53-miR-508-5p轴调控胃癌多药耐药
DOI：
10.18632/oncotarget.6374
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发表时间：
2016-01-05
期刊：
影响因子：
--
通讯作者：
Fan D
中科院分区：
文献类型：
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作者：
Shang Y;Feng B;Zhou L;Ren G;Zhang Z;Fan X;Sun Y;Luo G;Liang J;Wu K;Nie Y;Fan D
多药耐药（MDR）与胃癌治疗失败及预后不良有关。在之前的一项使用高通量功能筛选的研究中，我们鉴定了11种调节GC中MDR的microRNA（miRNAs），并发现miR-508- 5 p通过靶向ABCB 1和ZNRD 1逆转MDR。然而，miR-508- 5 p在化疗耐药GC细胞中减少的机制尚不清楚。在这项研究中，我们发现异位miR-27 b足以在体外和体内使肿瘤对化疗敏感。此外，miR-27 b直接靶向CCNG 1的3′非翻译区（3′-UTR），CCNG 1是一种众所周知的P53稳定性负调控因子。有趣的是，miR-27 b上调导致miR-508- 5 p表达增加，这种现象由CCNG 1和P53介导。进一步研究表明miR-508- 5 p受P53直接调控。因此，miR-27 b/CCNG 1/P53/miR-508- 5 p轴在GC相关MDR中起重要作用。此外，我们还检测了不同化疗敏感性的胃癌组织中miR-27 b和miR-508- 5 p的表达，发现miR-27 b和miR-508- 5 p表达上调的胃癌组织对化疗更敏感。总之，这些数据表明miR-27 b和miR-508- 5 p的组合代表MDR的潜在标志物。在未来的临床实践中，恢复miR-27 b和miR-508- 5 p水平可能有助于MDR逆转。
Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among gastric cancer (GC) patients. In a previous study using high-throughput functional screening, we identified 11 microRNAs (miRNAs) that regulate MDR in GC and found that miR-508-5p reversed MDR by targeting ABCB1 and ZNRD1. However, the mechanism by which miR-508-5p was decreased in chemo-resistant GC cells was unclear. In this study, we found that ectopic miR-27b is sufficient to sensitize tumors to chemotherapy in vitro and in vivo. Moreover, miR-27b directly targets the 3′ untranslated regions (3′-UTRs) of CCNG1, a well-known negative regulator of P53 stability. Interestingly, miR-27b up-regulation leads to increased miR-508-5p expression, and this phenomenon is mediated by CCNG1 and P53. Further investigation indicated that miR-508-5p is directly regulated by P53. Thus, the miR-27b/CCNG1/P53/miR-508-5p axis plays important roles in GC-associated MDR. In addition, miR-27b and miR-508-5p expression was detected in GC tissues with different chemo-sensitivities, and we found that tissues in which miR-27b and miR-508-5p are up-regulated are more sensitive to chemotherapy. Together, these data suggest that the combination of miR-27b and miR-508-5p represents a potential marker of MDR. Restoring the miR-27b and miR-508-5p levels might contribute to MDR reversion in future clinical practice.