Zhang Xin, Ren Dong, Wu Xianqiu, Lin Xi, Ye Liping, Lin Chuyong, Wu Shu, Zhu Jinrong, Peng Xinsheng, Song Libing
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China; Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen 529030, China.
Department of Orthopaedic Surgery/Orthopaedic Research Institute, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China.
Mol Ther Nucleic Acids. 2018 Jun 1;11:142-158. doi: 10.1016/j.omtn.2018.01.004. Epub 2018 Jan 31.
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 is 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 (GEM) in vitro and in vivo; conversely, inhibition of miR-1266 yielded the opposite effect. Importantly, silencing of miR-1266 restored the sensitivity of pancreatic cancer cells to GEM in a dose-dependent manner in vivo. Furthermore, our results demonstrate that miR-1266 promotes resistance of pancreatic cancer cells to GEM by targeting multiple negative regulators of the 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 a chemotherapeutic sensitizer, in combination with GEM, may serve as a rational regimen in the treatment of chemotherapy-resistant pancreatic cancer.
胰腺癌的特征是经过几个化疗周期后会产生化疗耐药性，这是导致胰腺癌治疗失败的一个主要问题。因此，有必要探索化疗耐药的具体机制以克服这一问题。在此，我们报告miR-1266在胰腺癌患者中显著升高，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在体外和体内对吉西他滨（GEM）的耐药性；相反，抑制miR-1266则产生相反的效果。重要的是，在体内沉默miR-1266以剂量依赖的方式恢复了胰腺癌细胞对GEM的敏感性。此外，我们的结果表明，miR-1266通过靶向STAT3和NF-κB通路的多个负调节因子促进胰腺癌细胞对GEM的耐药性，这些负调节因子包括SOCS3、PTPN11、ITCH和TNIP1，导致STAT3和NF-κB信号的组成性激活。因此，我们的研究结果阐明了miR-1266诱导胰腺癌化疗耐药的一种新机制，表明miR-1266可能用作化疗反应指标。抗miR-1266作为一种化疗增敏剂，与GEM联合使用，可能成为治疗化疗耐药胰腺癌的合理方案。
