Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Paediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Cancer Lett. 2019 Aug 10;457:28-39. doi: 10.1016/j.canlet.2019.05.006. Epub 2019 May 9.
The emergence of multiple drug resistance (MDR) is the main cause of chemotherapy failure in gastric cancer. In this study, to generate MDR gastric cancer cell lines, we exposed MKN45 and AGS gastric cancer cells to cisplatin, fluorouracil, and adriamycin. Through transcriptome sequencing, we found that interferon regulatory factor-1 (IRF-1) was expressed at significantly lower levels in the MDR cell lines than in the parental cell lines. We then established stable clones of MKN45 and SGC7901 cells with a doxycycline-inducible IRF-1 expression system and confirmed that IRF-1 overexpression efficiently reversed the MDR. Further analyses indicated that IRF-1 suppresses P-glycoprotein (P-gp) expression in vitro and in vivo, leading to an increase in chemotherapy drug retention. The results showed that IRF-1 bound to the promoter regions of P-gp gene and inhibited P-gp transcription. IFN-γ induced IRF-1-mediated downregulation of P-gp in gastric cancer cells. Finally, we demonstrated that the clinical correlation between IRF-1 and P-gp expression and that IRF-1 serves as an independent prognostic factor for patients with gastric cancer. We conclude that IRF-1 reverses the MDR trait of gastric cancer by downregulating P-gp, and this mechanism has potential treatment implications and is clinically actionable.
多药耐药（MDR）的出现是胃癌化疗失败的主要原因。在这项研究中，我们通过使 MKN45 和 AGS 胃癌细胞接触顺铂、氟尿嘧啶和阿霉素来产生 MDR 胃癌细胞系。通过转录组测序，我们发现干扰素调节因子-1（IRF-1）在 MDR 细胞系中的表达水平明显低于亲本细胞系。然后，我们建立了具有强力霉素诱导的 IRF-1 表达系统的 MKN45 和 SGC7901 细胞的稳定克隆，并证实 IRF-1 过表达有效地逆转了 MDR。进一步的分析表明，IRF-1 在体外和体内抑制 P-糖蛋白（P-gp）的表达，导致化疗药物保留增加。结果表明，IRF-1 结合 P-gp 基因的启动子区域并抑制 P-gp 转录。IFN-γ 诱导胃癌细胞中 IRF-1 介导的 P-gp 下调。最后，我们证明了 IRF-1 和 P-gp 表达之间的临床相关性，以及 IRF-1 是胃癌患者的独立预后因素。我们得出结论，IRF-1 通过下调 P-gp 逆转了胃癌的 MDR 特征，这种机制具有潜在的治疗意义和临床可操作性。
