Dong Qianze, Fu Lin, Zhao Yue, Liu Yang, Li Qingchang, Qiu Xueshan, Wang Enhua
Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China.
Oncotarget. 2017 Jul 7;8(33):55135-55146. doi: 10.18632/oncotarget.19069. eCollection 2017 Aug 15.
Radiotherapy is widely used for treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the role of Derlin-1 on the sensitivity of ESCC to radiotherapy and its underlying mechanism. We examined the clinical significance of Derlin-1 in 125 ESCC tissues. We found that Derlin-1 protein was higher in ESCC tissues than that in normal esophageal epithelial tissues. Derlin-1 overexpression was correlated with chemoradiotherapy resistance in ESCC patients and served an independent predictor for short overall survival. siRNA knockdown and plasmid transfection were carried out in ESCC cell lines. Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth. Derlin-1 overexpression in Eca-109 cells dramatically enhanced its resistance to radiotherapy with decreased apoptosis rate. On the contrary, Derlin-1 depletion in TE-1 cell line showed the opposite effects. In addition, radioresistance conferred by Derlin-1 was attributed to its role of activating AKT/Bcl-2 signaling pathway and reducing caspase3 cleavage. Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance. Furthermore, Derlin-1 could interact with PI3K p110α in ESCC cell lines. Taken together, Our data demonstrate that Derlin-1 overexpression predicts poor prognosis and protects ESCC from irradiation induced apoptosis through PI3K/AKT/Bcl-2 signaling pathway. Derlin-1 may serve as a novel predictor for radiosentivity and a molecular target for ESCC.
放射疗法广泛应用于食管鳞状细胞癌（ESCC）的治疗。本研究旨在探讨Derlin-1在ESCC放疗敏感性中的作用及其潜在机制。我们检测了125例ESCC组织中Derlin-1的临床意义。我们发现，ESCC组织中Derlin-1蛋白水平高于正常食管上皮组织。Derlin-1过表达与ESCC患者的放化疗耐药相关，是总生存期短的独立预测因素。在ESCC细胞系中进行了siRNA敲低和质粒转染实验。敲低Derlin-1抑制细胞生长，而过表达则促进细胞生长。Eca-109细胞中Derlin-1过表达显著增强其对放疗的抗性，凋亡率降低。相反，TE-1细胞系中Derlin-1敲低则产生相反的效果。此外，Derlin-1赋予的放射抗性归因于其激活AKT/Bcl-2信号通路和减少caspase3裂解的作用。阻断AKT信号减弱了Derlin-1对放射抗性的作用。此外，Derlin-1可与ESCC细胞系中的PI3K p110α相互作用。综上所述，我们的数据表明，Derlin-1过表达预示预后不良，并通过PI3K/AKT/Bcl-2信号通路保护ESCC免受辐射诱导的凋亡。Derlin-1可能作为ESCC放射敏感性的新型预测指标和分子靶点。
