Selenoprotein GPX1 is a prognostic and chemotherapy-related biomarker for brain lower grade glioma.

Objective: Glutathione peroxidase 1 (GPX1) is a major selenoprotein in most animal tissues, primarily expressed in the cytoplasm and mitochondria of cells and peroxidase structures of certain cells. GPX1 expression is highly correlated with carcinogenesis and disease progression. The goal of the study was to determine the association between GPX1 expression and tumor therapy, and to identify GPX1 prognostic value in various malignancies.

Methods: The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA) databases were used to detect the levels of GPX1 expression in human tumor tissues and normal tissues. Indeed, correlations between GPX1 and tumor purity, tumor mutation burden (TMB), microsatellite instability (MSI), and DNA mismatch repair genes (MMRs) were explored using the TCGA cohort. Functional and enrichment analyses were performed by the GeneMANIA database and Gene Set Enrichment Analysis (GSEA), respectively. Cox regression models and Kaplan - Meier curves were used to screen for independent risk factors and estimate brain lower-grade glioma (LGG) survival probability. The Chinese Glioma Genome Atlas (CGGA) database was used to determine whether GPX1 had a race-specific effect on overall survival (OS) in LGG. The cross-interaction between GPX1 and chemoradiotherapy on LGG OS was determined by Kaplan - Meier curves. Logistic regression models of multiplicative interactions were constructed. Furthermore, the relationship between GPX1 and LGG treatment regimens was also explored through the Genomics of Drug Sensitivity in Cancer (GDSC) database.

Results: GPX1 was highly expressed in various tumors, GPX1 overexpression was significantly correlated with the poor prognosis of LGG. GPX1 was found to be an independent predictive factor for LGG in both univariate and multivariate Cox models. The nomogram showed a high predictive accuracy (C-index: 0.804, 95% CI: 0.74-0.86). In addition, GPX1 was significantly associated with TMB, MSI, and MMRs in diverse cancers. GPX1 was involved in IL6/JAK/STAT3, inflammatory response, and apoptosis signaling pathways. Besides, non-radiotherapy, chemotherapy, and low GPX1 expression were important factors affecting the better prognosis of LGG. GPX1 acted as a tumor promoter, which has taken the worst effect on LGG survival, but a multiplicative interaction of GPX1*chemoradiotherapy may improve the poor clinical outcome. GPX1 was negatively correlated with the half inhibition concentration (IC50) of temozolomide (TMZ) (Spearman = -0.44, P = 4.52 ×10).

Conclusion: In LGG patients, high GPX1 expression was linked to a shorter OS. The interaction between GPX1 and chemoradiotherapy exhibits a beneficial clinical effect and chemotherapy was recommended for LGG patients, especially for those with high GPX1 expression. Besides, high GPX1 expression can predict TMZ sensitivity in LGG, providing potential evidence for chemotherapy. On the whole, this study presents a wealth of biological as well as clinical significance for the roles of GPX1 in human tumors, particularly in LGG.