Peng W-X, Wan Y-Y, Gong A-H, Ge L, Jin J, Xu M, Wu C-Y
Department of Oncology, the Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
Department of Cell biology, School of Medicine, Jiangsu University, Zhenjiang, China.
Oncogenesis. 2017 Jan 30;6(1):e292. doi: 10.1038/oncsis.2016.91.
Although hepatocellular carcinoma (HCC) is usually response to radiation therapy, radioresistance is still the major obstacle that limits the efficacy of radiotherapy for HCC patients. Therefore, further investigation of underlying mechanisms in radioresistant HCC cells is warranted. In this study, we determined the effect of early growth response factor (Egr-1) on irradiation-induced autophagy and radioresistance in HCC cell lines SMMC-7721 and HepG2. We showed that autophagy-related gene 4B (Atg4B) is induced by Egr-1 upon ionizing radiation (IR) in HCC cells. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) revealed that Egr-1 binds to the Atg4B promoter to upregulate its expression in HCC cells. Suppression of Egr-1 function by dominant-negative Egr-1 dampens IR-induced autophagy, cell migration, and increases cell sensitivity to radiotherapy. Together, these results suggest that Egr-1 contributes to HCC radioresistance through directly upregulating target gene Atg4B, which may serve as a protective mechanism by preferential activation of the autophagy.
尽管肝细胞癌（HCC）通常对放射治疗有反应，但放射抗性仍然是限制HCC患者放射治疗疗效的主要障碍。因此，有必要进一步研究放射抗性HCC细胞的潜在机制。在本研究中，我们确定了早期生长反应因子（Egr-1）对HCC细胞系SMMC-7721和HepG2中辐射诱导的自噬和放射抗性的影响。我们发现，电离辐射（IR）后，HCC细胞中Egr-1可诱导自噬相关基因4B（Atg4B）。荧光素酶报告基因检测和染色质免疫沉淀（ChIP）显示，Egr-1与Atg4B启动子结合，上调其在HCC细胞中的表达。显性负性Egr-1抑制Egr-1功能可减弱IR诱导的自噬、细胞迁移，并增加细胞对放射治疗的敏感性。总之，这些结果表明，Egr-1通过直接上调靶基因Atg4B促进HCC的放射抗性，这可能是一种通过优先激活自噬的保护机制。
