Abstract
BackgroundRadiation therapy is the primary method of treatment for glioblastoma (GBM). Therefore, the suppression of radioresistance in GBM cells is of enormous significance. Ribophorin II (RPN2), a protein component of an N-oligosaccharyl transferase complex, has been associated with chemotherapy drug resistance in multiple cancers, including GBM. However, it remains unclear whether this also plays a role in radiation therapy resistance in GBM.MethodsWe conducted a bioinformatic analysis of RPN2 expression using the UCSC Cancer Genomics Browser and GEPIA database and performed an immunohistochemical assessment of RPN2 expression in biopsy specimens from 34 GBM patients who had received radiation-based therapy. We also studied the expression and function of RPN2 in radiation-resistant GBM cells.ResultsWe found that RPN2 expression was upregulated in GBM tumors and correlated with poor survival. The expression of RPN2 was also higher in GBM patients with tumor recurrence, who were classified to be resistant to radiation therapy. In the radiation-resistant GBM cells, the expression of RPN2 was also higher than in the parental cells. Depletion of RPN2 in resistant cells can sensitize these cells to radiation-induced apoptosis, and overexpression of RPN2 had the reverse effect. Myeloid cell leukemia 1 (MCL1) was found to be the downstream target of RPN2, and contributed to radiation resistance in GBM cells. Furthermore, STAT3 was found to be the regulator of MCL1, which can be activated by RPN2 dysregulation.ConclusionOur study has revealed a novel function of RPN2 in radiation-resistant GBM, and has shown that MCL1 depletion or suppression could be a promising method of therapy to overcome the resistance promoted by RPN2 dysregulation.
Highlights
Radiation therapy is the primary method of treatment for glioblastoma (GBM)
Abnormal expression of Ribophorin II (RPN2) is correlated to poor survival of GBM patients To study the role of RPN2 in GBM radiotherapy, we first determined the expression of RPN2 in GBM by analyzing mRNA data in the Cancer Genome Atlas (TCGA) database
Our analysis of GEPIA data indicated that high expression of RPN2 is associated with poorer survival in GBM patients, which strongly suggests that abnormal expression of RPN2 plays an important role in GBM
Summary
Radiation therapy is the primary method of treatment for glioblastoma (GBM). the suppression of radioresistance in GBM cells is of enormous significance. Ribophorin II (RPN2), a protein component of an N-oligosaccharyl transferase complex, has been associated with chemotherapy drug resistance in multiple cancers, including GBM. It remains unclear whether this plays a role in radiation therapy resistance in GBM. Radiation therapy remains a primary method of treatment for GBM (Ghotme et al, 2017), and the reduction of radioresistance in GBM cells and therapeutic targets is of huge significance. Gastric cancers with high RPN2 expression have exhibited dramatically higher recurrence rates and lower 5-year survival rates relative to those with low expression (Fujimoto et al, 2017) These observations suggest that RPN2 expression could serve as a predictive biomarker for chemotherapy resistance. The correlation of RPN2 expression and radiotherapy resistance in GBM remains unknown
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