Li Jing, Li Xiaocui, Wang Jingpu, Wang Yuan, Qiu Haifeng
Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
APMIS. 2015 Jul;123(7):562-70. doi: 10.1111/apm.12387. Epub 2015 Apr 24.
We previously reported that microRNA-218 was frequently lost in cervical cancer and restoration of microRNA-218 increased cellular radio-sensitivity via inhibiting. Herein, we aim to investigate the effects of microRNA-218 on cellular response to mTOR inhibition. The expression of microRNA-218 and Rictor were measured by Taqman PCR and real time PCR in a panel of 15 cervical cancer tissues. MicroRNA-218 was stably overexpressed in four cervical cancer cell lines and a series of in vitro and in vivo experiments were performed to investigate cellular sensitivity to Rapamycin. In primary cultured cervical cancer cells, the expression of microRNA-218 was negatively correlated with the mRNA level of Rictor, which predicted cellular sensitivity to Rapamycin (p = 0.002, R(2) = 0.6810). In vitro, overexpression of microRNA-218 significantly reduced the level of Rictor and enhanced the growth-inhibition, cell cycle arrest, and apoptosis induced by Rapamycin. In vivo, overexpression of microRNA-218 further enhanced the suppressive effects of Rapamycin on tumor growth. In conclusion, we demonstrated that microRNA-218 could re-sensitize cervical cancer to Rapamycin through targeting Rictor. Moreover, patients with loss of microRNA-218 presented notable resistance to Rapamycin, indicating that microRNA-218 might be a valid marker for patients-stratification in future clinical trials.
我们之前报道过，微小RNA-218在宫颈癌中经常缺失，而微小RNA-218的恢复通过抑制作用增加了细胞的放射敏感性。在此，我们旨在研究微小RNA-218对细胞对mTOR抑制反应的影响。通过Taqman PCR和实时PCR检测了15例宫颈癌组织中微小RNA-218和Rictor的表达。在四种宫颈癌细胞系中稳定过表达微小RNA-218，并进行了一系列体外和体内实验以研究细胞对雷帕霉素的敏感性。在原代培养的宫颈癌细胞中，微小RNA-218的表达与Rictor的mRNA水平呈负相关，Rictor可预测细胞对雷帕霉素的敏感性（p = 0.002，R² = 0.6810）。在体外，微小RNA-218的过表达显著降低了Rictor的水平，并增强了雷帕霉素诱导的生长抑制、细胞周期阻滞和细胞凋亡。在体内，微小RNA-218的过表达进一步增强了雷帕霉素对肿瘤生长的抑制作用。总之，我们证明了微小RNA-218可通过靶向Rictor使宫颈癌对雷帕霉素重新敏感。此外，微小RNA-218缺失的患者对雷帕霉素表现出明显的抗性，这表明微小RNA-218可能是未来临床试验中患者分层的有效标志物。
