1. Inhibition of human positive cofactor 4 radiosensitizes human esophageal squmaous cell carcinoma cells by suppressing XLF-mediated nonhomologous end joining
- Author
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Bailu Zhang, Zhiyong Yuan, Dong Qian, T. S. Zhao, C. Jiang, Dan Xie, L. J. Zhao, J. M. Le Blanc, C. Xue, X. L. Zeng, J. H. Hao, Huijuan Wang, P. Wang, Bo Lu, Yan Guo, and Mao-Bin Meng
- Subjects
Male ,Cancer Research ,DNA End-Joining Repair ,Esophageal Neoplasms ,DNA repair ,Immunology ,Down-Regulation ,Mitosis ,Apoptosis ,Biology ,Radiation Tolerance ,Cellular and Molecular Neuroscience ,Radioresistance ,Cell Line, Tumor ,Radiation, Ionizing ,medicine ,Gene silencing ,Humans ,DNA Breaks, Double-Stranded ,Radiosensitivity ,Gene Silencing ,Mitotic catastrophe ,neoplasms ,Proportional Hazards Models ,Cancer ,Cell Biology ,Middle Aged ,medicine.disease ,Molecular biology ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,digestive system diseases ,Non-homologous end joining ,DNA-Binding Proteins ,DNA Repair Enzymes ,Multivariate Analysis ,Cancer research ,Carcinoma, Squamous Cell ,Female ,Original Article ,Esophageal Squamous Cell Carcinoma ,Transcription Factors - Abstract
Radiotherapy has the widest application to esophageal squamous cell carcinoma (ESCC) patients. Factors associated with DNA damage repair have been shown to function in cell radiosensitivity. Human positive cofactor 4 (PC4) has a role in nonhomologous end joining (NHEJ) and is involved in DNA damage repair. However, the clinical significance and biological role of PC4 in cancer progression and cancer cellular responses to chemoradiotherapy (CRT) remain largely unknown. The aim of the present study was to investigate the potential roles of PC4 in the radiosensitivity of ESCC. In this study, we showed that knockdown of PC4 substantially increased ESCC cell sensitivity to ionizing radiation (IR) both in vitro and in vivo and enhanced radiation-induced apoptosis and mitotic catastrophe (MC). Importantly, we demonstrated that silencing of PC4 suppressed NHEJ by downregulating the expression of XLF in ESCC cells, whereas reconstituting the expression of XLF protein in the PC4-knockdown ESCC cells restored NHEJ activity and radioresistance. Moreover, high expression of PC4 positively correlated with ESCC resistance to CRT and was an independent predictor for short disease-specific survival of ESCC patients in both of our cohorts. These findings suggest that PC4 protects ESCC cells from IR-induced death by enhancing the NHEJ-promoting activity of XLF and could be used as a novel radiosensitivity predictor and a promising therapeutic target for ESCCs.
- Published
- 2014