An Y, Zhang Z, Shang Y, Jiang X, Dong J, Yu P, Nie Y, Zhao Q
1] State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China [2] Department of General Surgery, General Hospital of Jinan Military Command, Jinan, China [3] Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
1] State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, 127 Changle Western Road, Xi'an, Shaanxi 710032, China [2] Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, Zhejiang 315211, China.
Cell Death Dis. 2015 May 21;6(5):e1766. doi: 10.1038/cddis.2015.123.
Chemotherapy is an important treatment modality for gastric cancer (GC); however, it usually fails because of drug resistance, especially multidrug resistance (MDR). Previously, we found a novel subset of MDR-associated microRNAs (miRNAs) through high-throughput functional screening. In this report, we investigated the exact roles and mechanisms of miR-23b-3p in the MDR of GC. Using gain or loss-of-function in in vitro and in vivo experiments, we found that overexpression of miR-23b-3p reversed cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumors to chemotherapy in vivo. Reporter gene assay and western blot analysis showed that ATG12 and HMGB2 were the direct targets of miR-23b-3p. Meanwhile, ATG12 and HMGB2 were positively associated with the occurrence of autophagy. Reducing the expression of these target genes by siRNA or inhibition of autophagy both sensitized GC cells to chemotherapy. These findings suggest that a miR-23b-3p/ATG12/HMGB2/autophagy-regulatory loop has a critical role in MDR in GC. In addition, miR-23b-3p could be used as a prognostic factor for overall survival in GC. In conclusion, our data demonstrated that miR-23b-3p inhibited autophagy mediated by ATG12 and HMGB2 and sensitized GC cells to chemotherapy, and suggested the potential application of miR-23b-3p in drug resistance prediction and treatment.
化疗是胃癌（GC）的一种重要治疗方式；然而，它通常因耐药性，尤其是多药耐药（MDR）而失败。此前，我们通过高通量功能筛选发现了一个与MDR相关的新型微小RNA（miRNA）子集。在本报告中，我们研究了miR-23b-3p在GC的MDR中的具体作用和机制。通过体外和体内实验的功能获得或缺失研究，我们发现miR-23b-3p的过表达在体外逆转了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。报告基因检测和蛋白质印迹分析表明，ATG12和HMGB2是miR-23b-3p的直接靶点。同时，ATG12和HMGB2与自噬的发生呈正相关。通过小干扰RNA降低这些靶基因的表达或抑制自噬均使GC细胞对化疗敏感。这些发现表明，一个miR-23b-3p/ATG12/HMGB2/自噬调节环在GC的MDR中起关键作用。此外，miR-23b-3p可作为GC总生存的一个预后因素。总之，我们的数据表明，miR-23b-3p抑制由ATG12和HMGB2介导的自噬并使GC细胞对化疗敏感，并提示miR-23b-3p在耐药性预测和治疗中的潜在应用。
