Pancreatic cancer is characterized by chemoresistance after several cycles of chemotherapy, which is a major issue responsible for treatment failure of pancreatic cancer. Therefore, it’s necessary to explore the specific mechanism underlying chemotherapeutic resistance to overcome this issue. Here we report that miR-1266 is dramatically elevated and correlates with poor survival and chemotherapy response in pancreatic cancer patients. Upregulation of miR-1266 enhanced the chemoresistance of pancreatic cancer cells to gemcitabine in vitro and in vivo; conversely, inhibition of miR-1266 yielded an opposite effect. Importantly, silencing miR-1266 restored the sensitivity of pancreatic cancer cells to gemcitabine in a dose-dependent manner in vivo. Furthermore, our results demonstrated miR-1266 promoted the resistance of pancreatic cancer cells to gemcitabine via targeting multiple negative regulators of STAT3 and NF-κB pathways, including SOCS3, PTPN11, ITCH, and TNIP1, leading to constitutive activation of STAT3 and NF-κB signaling. Thus, our findings clarify a novel mechanism by which miR-1266 induces chemotherapeutic resistance in pancreatic cancer, indicating that miR-1266 may be used as chemotherapeutic response indicator. Antagomir-1266 as chemotherapeutic sensitizer in combination with gemcitabine may serve as a rational regimen in the treatment of chemotherapeutic resistant pancreatic cancer.

胰腺癌的特征在于经过数次化疗后的化学耐药性，这是导致胰腺癌治疗失败的主要问题。因此，有必要探索化学疗法抗性的具体机制以克服这一问题。在这里我们报道，胰腺癌患者中miR-1266显着升高，并且与较差的生存率和化疗反应相关。miR-1266的上调增强了胰腺癌细胞对吉西他滨的体外和体内化学耐药性; 相反，抑制miR-1266产生相反的效果。重要的是，沉默miR-1266在体内以剂量依赖性方式恢复了胰腺癌细胞对吉西他滨的敏感性。。此外，我们的结果表明，miR-1266通过靶向STAT3和NF-κB途径的多个负调控因子（包括SOCS3，PTPN11，ITCH和TNIP1）来促进胰腺癌细胞对吉西他滨的耐药性，从而导致STAT3和NF-κB的组成性活化信号。因此，我们的发现阐明了miR-1266诱导胰腺癌化疗耐药的新机制，表明miR-1266可用作化疗反应指标。Antagomir-1266作为化疗增敏剂与吉西他滨合用可作为治疗耐药化疗性胰腺癌的合理方案。