The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer |
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Authors: | Yulong Shang Bin Feng Lin Zhou Gui Ren Zhiyong Zhang Xing Fan Yi Sun Guanhong Luo Jie Liang Kaichun Wu Yongzhan Nie Daiming Fan |
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Affiliation: | 1. State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi''an 710032, China;2. The 88th Hospital of PLA, Tai''an 271001, China;3. Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi''an 710032, China;4. Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi''an, 710032, China |
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Abstract: | 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. |
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Keywords: | gastric cancer multidrug resistance miR-27b miR-508-5p CCNG1 |
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