Abstract
Radiotherapy is one of the cornerstone of the glioblastoma treatment paradigm. However, the resistance of tumor cells to radiation results in poor survival. The mechanism of radioresistance has not been fully elucidated. This study aimed to screen the differential expressed genes related with radiosensitivity. The differentially expressed genes were screened based on RNA sequencing in 15 pairs of primary and recurrent glioblastoma that have undergone radiotherapy. Candidate genes were validated in 226 primary and 134 recurrent glioblastoma (GBM) obtained from the Chinese Glioma Genome Atlas (CGGA) database. RNA and protein expression were verified by Quantitative Real-time PCR (qPCR) and western blot in irradiated GBM cell lines. The candidate gene was investigated to explore the relationship between mRNA levels and clinical characteristics in the CGGA and The Cancer Genome Atlas dataset. Kaplan-Meier survival analysis and Cox regression analysis were used for survival analysis. Gene ontology and KEGG pathway analysis were used for bioinformatics analysis. Four genes (TMEM59L, Gelsolin, ZBTB7A and ATX) were screened. TMEM59L expression was significantly elevated in recurrent glioblastoma and lower in normal brain tissue. We selected TMEM59L as the target gene for further study. The increasing of TMEM59L expression induced by radiation was confirmed by mRNA and western blot in irradiated GBM cell. Further investigation revealed that high expression of TMEM59L was enriched in IDH mutant and MGMT methylated gliomas and associated with a better prognosis. Gene ontology and KEGG pathway analysis revealed that TMEM59L was closely related to the DNA damage repair and oxidative stress respond process. We speculated that the high expression of TMEM59L might enhance radiotherapy sensitivity by increasing ROS-induced DNA damage and inhibiting DNA damage repair process.