Li Wen-Feng, Zhang Li, Li Hai-Ying, Zheng Si-Si, Zhao Liang
Department of Radiation Oncology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
PLoS One. 2014 Apr 11;9(4):e94751. doi: 10.1371/journal.pone.0094751. eCollection 2014.
Cancer cells that survive fractionated irradiation can be radioresistant and cause tumor recurrence. However, the molecular mechanisms underlying the development of radioresistance in cancer cells remain elusive. The aim of this study was to investigate the role of WISP-1 in the development of radioresistance in esophageal carcinoma during fractionated irradiation. Radioresistant esophageal cancer cells were generated from normal esophageal cancer cells via fractionated irradiation, and expression levels of related proteins were determined by Western blot. Radiosensitivity of cells was established by clonogenic cell survival assays, and cell cycle distribution was evaluated by flow cytometry. Protein distributions were determined by immunofluorescence, and cell toxicity was evaluated by cell counting kit-8 assays. In vivo validations were performed in a xenograft transplantation mouse model. Our data indicate that WISP-1 plays an important role in the development of radioresistance in esophageal cancer cells during fractionated irradiation. The overexression of WISP-1 in esophageal cancer cells was associated with radioresistance. Depletion of extracellular WISP-1 by antibody neutralizing reversed radioresistance and directly induced mitotic catastrophe resulting in cell death. WISP-1 may be a candidate therapeutic target in the treatment of recurrent esophageal carcinoma after radiotherapy.
分次照射后存活的癌细胞可能具有放射抗性，并导致肿瘤复发。然而，癌细胞放射抗性产生的分子机制仍不清楚。本研究旨在探讨WISP-1在食管癌分次照射过程中放射抗性形成中的作用。通过分次照射从正常食管癌细胞中产生放射抗性食管癌细胞，并通过蛋白质免疫印迹法测定相关蛋白的表达水平。通过克隆形成细胞存活试验确定细胞的放射敏感性，并通过流式细胞术评估细胞周期分布。通过免疫荧光确定蛋白质分布，并通过细胞计数试剂盒-8试验评估细胞毒性。在异种移植小鼠模型中进行体内验证。我们的数据表明，WISP-1在食管癌细胞分次照射过程中放射抗性的形成中起重要作用。食管癌细胞中WISP-1的过表达与放射抗性相关。通过抗体中和作用耗尽细胞外WISP-1可逆转放射抗性，并直接诱导有丝分裂灾难导致细胞死亡。WISP-1可能是放疗后复发性食管癌治疗的候选治疗靶点。
