Elevated expression of AKR1C3 leads esophageal cancer resistant to ionizing radiation via modulation of oxidative stress (KY170)

With the aim to elucidate the etiology of radioresistance, we explored the genetic alterations in non-radioresistant vs. resistant esophageal cancer cells acquired by long-term fractionated radiation. We found AKR1C3, an aldo-keto reductase expressed seldom in most human tissues, expressed higher in radioresistance-acquired cells. Suppression of AKR1C3 via RNAi or its chemical inhibitors restored the sensitivity of the acquired tumor cells and xenograft nude mice to ionizing radiation (IR). We also found the potential involvement of AKR1C3 in removal of cellular ROS and explain, at least partially, the acquired radioresistance by AKR1C3 overexpression. Genome-wide profiling of gene expression in KY170R v. KY170 and TE13R v. TE13 using Illumine Human-6 V3 microarray indicated that over 900 genes were found to be remarkably differentiated. Among them, AKR1C3, an aldo-keto reductase existing at a low level in most human tissues, attracted our attention due to its significant expression in both radioresistant cells.

为阐明放射抵抗的发病机制，我们对经长期分次辐射诱导获得的非放射抵抗型与放射抵抗型食管癌细胞的遗传改变展开了探究。研究发现，在大多数人体组织中低表达的醛酮还原酶（aldo-keto reductase）AKR1C3，在放射抵抗型诱导细胞中的表达水平显著升高。通过RNA干扰（RNA interference, RNAi）或其化学抑制剂抑制AKR1C3的表达，可使诱导获得的肿瘤细胞及裸鼠异种移植瘤模型恢复对电离辐射（ionizing radiation, IR）的敏感性。我们还发现AKR1C3可能参与细胞活性氧（reactive oxygen species, ROS）的清除过程，这至少部分解释了AKR1C3过表达所介导的获得性放射抵抗机制。利用Illumina Human-6 V3基因芯片对KY170R与KY170、TE13R与TE13进行全基因组基因表达谱分析，结果显示共有超过900个基因存在显著表达差异。其中，上述醛酮还原酶AKR1C3因在两种放射抵抗型细胞中均呈现显著高表达而受到我们的关注。