Fan Liyuan, Wang Juan, Cao Qiang, Ding Xiuping, Li Baosheng
Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences Jinan 250117, China.
Cheeloo College of Medicine, Shandong University Jinan 250112, China.
Am J Cancer Res. 2020 Jan 1;10(1):314-335. eCollection 2020.
Radiosensitivity varies among patients with non-small cell lung cancer (NSCLC). In this work, we aimed to investigate microRNAs associated with this heterogeneity among individuals. We selected miR-1246 from the microRNAs that were revealed by microarray experiments to be differentially expressed between radioresistant and parental cell lines. Both intracellular and extracellular miR-1246 was found to be upregulated after irradiation in a time-dependent pattern, resulting in increased radioresistance of NSCLC cells. We found that mTOR was a direct target gene of miR-1246, which mediated miR-1246-induced autophagy activation. Yin Yang-1 (YY1) was demonstrated to be a new transcription factor that regulates miR-1246 and CDR1as was found to be a circular RNA that sequesters miR-1246, which was confirmed in NSCLC cells and clinical samples. Finally, combining these data with the results from The Cancer Genome Atlas (TCGA), we verified that miR-1246 could be used as a biomarker to predict NSCLC patients' radiosensitivity and prognosis. Overall, our study fully investigated the effect of miR-1246 on radiosensitivity and comprehensively investigated the potential of miR-1246 as a prognostic biomarker and radiotherapy sensitization target.
非小细胞肺癌（NSCLC）患者的放射敏感性各不相同。在本研究中，我们旨在探究与个体间这种异质性相关的微小RNA。我们从微阵列实验揭示的、在放射抗性细胞系和亲本细胞系之间差异表达的微小RNA中选择了miR-1246。结果发现，照射后细胞内和细胞外的miR-1246均呈时间依赖性上调，导致NSCLC细胞的放射抗性增加。我们发现mTOR是miR-1246的直接靶基因，其介导了miR-1246诱导的自噬激活。阴阳1（YY1）被证明是一种调节miR-1246的新转录因子，且发现CDR1as是一种可隔离miR-1246的环状RNA，这在NSCLC细胞和临床样本中得到了证实。最后，将这些数据与癌症基因组图谱（TCGA）的结果相结合，我们验证了miR-1246可作为预测NSCLC患者放射敏感性和预后的生物标志物。总体而言，我们的研究全面调查了miR-1246对放射敏感性的影响，并全面研究了miR-1246作为预后生物标志物和放射治疗增敏靶点的潜力。
