柠檬酸转运体SLC25A1对食管鳞癌细胞体外放射敏感性的影响及其分子机制

doi:10.3969/j.issn.1004-616x.2020.02.009

Abstract

Abstract: OBJECTIVE: To investigate the effect and molecular mechanism of mitochondrial citrate transporter SLC25A1 on sensitivity of esophageal squamous cell carcinoma to radiotherapy in vitro. METHODS: The Cancer Genome Atlas (TCGA) tumor tissue database and UALCAN interactive network tool were used to compare differences in SLC25A1 expression between 184 cases of esophageal cancer and 11 cases of normal tissues. Radioresistant esophageal carcinoma cell line and the control were established by multiple round of X-ray sublethal dose exposures. Radioresistance and radiosensitivities were characterized by the radiation clonal survival assay and the linear quadratic target model. Morphologic changes of cell apoptosis were observed by fluorescence microscopy using the Hoechst 33258 staining after multiple X-ray exposures at a total dose of 6.0 Gy. Flow cytometry was used to detect levels of reactive oxygen species after the same X-ray exposures. Western blotting was used to analyze the expression alteration of levels of phosphor-H2AX and phosphor-DNA-PKcs,and the key signal kinases in DNA repair by SLC25A1 knockdown with lentivirus vector carrying small hairpin interfering RNA. RESULTS: A comparative analysis of TCGA tumor tissue database confirmed that the expression level of SLC25A1 mRNA in esophageal cancer tissues was 1.65-folds higher than that in normal esophageal tissues (P=1.64×10^-4). The expression level of SLC25A1 protein was increased by 2.36-folds when compared with the control (P < 0.05). The apoptosis rate of esophageal cancer cell lines with stable SLC25A1 expression compared to the control was increased by 1.58-folds (P < 0.05). ROS level in the SLC25A1 knockdown radioresistant esophageal carcinoma cell line was decreased by (65.3±14.3)% (P=0.007). Levels of phosphorylation of H2AX (Ser139) and DNA-PKCs (Ser2056) in SLC25A1 knockdown radioresistant esophageal carcinoma cell lines were significantly reduced when compared with the control (all P < 0.05). CONCLUSION: SLC25A1 may be an oncogene involved in tumor pathogenesis and radiation resistance. The data suggest that it can inhibit DNA damage repair and induce cell apoptosis by down-regulating reactive oxygen species,and can serve as a potential molecular target for radiation sensitization of esophageal squamous cell carcinoma.

Key words: SLC25A1, esophageal squamous cell carcinoma, radiosensitization, reactive oxygen species, DNA repair

CLC Number:

R735.1

SHI Pan, LIN Chonghua, SHU Yifang, QU Jiaquan, SONG Shuliang. Role of mitochondrial citrate transporter SLC25A1 in radiosensitivity of human esophageal squamous cell carcinoma in vitro[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2020, 32(2): 132-138.

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Role of mitochondrial citrate transporter SLC25A1 in radiosensitivity of human esophageal squamous cell carcinoma in vitro

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