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Expression of TMEM59L associated with radiosensitive in glioblastoma
Dezhi Gao1,2, Peng Wang1,3, Lin Zhi1,3
1Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, No. 119 South Fourth Ring West Road, Fengtai District, Beijing 100070, China.
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.
Insights
Researchers identified TMEM59L as a key gene in glioblastoma radioresistance. Higher TMEM59L expression correlates with better prognosis and may enhance radiotherapy sensitivity by promoting DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) is a primary brain tumor with poor survival rates, often linked to tumor cell resistance to radiotherapy.
- Understanding the molecular mechanisms of radioresistance is crucial for improving GBM treatment outcomes.
Purpose of the Study:
- To identify differentially expressed genes associated with glioblastoma radiosensitivity using RNA sequencing.
- To validate candidate genes and investigate the role of TMEM59L in GBM radioresistance and patient prognosis.
Main Methods:
- RNA sequencing of primary and recurrent glioblastoma pairs.
- Validation of candidate genes in large patient cohorts (CGGA, TCGA).
- Quantitative Real-time PCR, Western blot, survival analysis, and bioinformatics analyses (GO, KEGG).
Main Results:
- Four candidate genes were identified, with TMEM59L showing significantly elevated expression in recurrent GBM.
- TMEM59L expression increased upon radiation in GBM cells and was associated with IDH mutations and MGMT methylation.
- High TMEM59L expression correlated with better prognosis and was linked to DNA damage repair and oxidative stress pathways.
Conclusions:
- TMEM59L is a potential biomarker for glioblastoma radiosensitivity and prognosis.
- High TMEM59L expression may enhance radiotherapy efficacy by increasing reactive oxygen species (ROS)-induced DNA damage and impairing DNA repair mechanisms.
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