Identification and validation of a novel prognostic signature based on mitochondria and oxidative stress related genes for glioblastoma

Abstract

Background Mitochondria represent a major source of reactive oxygen species (ROS) in cells, and the direct increase in ROS content is the primary cause of oxidative stress, which plays an important role in tumor proliferation, invasion, angiogenesis, and treatment. However, the relationship between mitochondrial oxidative stress-related genes and glioblastoma (GBM) remains unclear. This study aimed to investigate the value of mitochondria and oxidative stress-related genes in the prognosis and therapeutic targets of GBM. Methods We retrieved mitochondria and oxidative stress-related genes from several public databases. The LASSO regression and Cox analyses were utilized to build a risk model and the ROC curve was used to assess its performance. Then, we analyzed the correlation between the model and immunity and mutation. Furthermore, CCK8 and EdU assays were utilized to verify the proliferative capacity of GBM cells and flow cytometry was used to analyze apoptosis rates. Finally, the JC-1 assay and ATP levels were utilized to detect mitochondrial function, and the intracellular ROS levels were determined using MitoSOX and BODIPY 581/591 C11. Results 5 mitochondrial oxidative stress-related genes (CTSL, TXNRD2, NUDT1, STOX1, CYP2E1) were screened by differential expression analysis and Cox analysis and incorporated in a risk model which yielded a strong prediction accuracy (AUC value = 0.967). Furthermore, this model was strongly related to immune cell infiltration and mutation status and could identify potential targeted therapeutic drugs for GBM. Finally, we selected NUDT1 for further validation in vitro. The results showed that NUDT1 was elevated in GBM, and knockdown of NUDT1 inhibited the proliferation and induced apoptosis of GBM cells, while knockdown of NUDT1 damaged mitochondrial homeostasis and induced oxidative stress in GBM cells. Conclusion Our study was the first to propose a prognostic model of mitochondria and oxidative stress-related genes, which provided potential therapeutic strategies for GBM patients.

Mitochondria-related chemoradiotherapy resistance genes-based machine learning model associated with immune cell infiltration on the prognosis of esophageal cancer and its value in pan-cancer

“…Previous research has demonstrated that removing MRPL37 increases susceptibility to paclitaxel [24] . Cathepsin L (CTSL) is a mitochondrial stress response marker linked to mitochondrial oxidative stress [ 25 , 26 ]. CTSL, a cysteine protease, plays an important role in tumor cell resistance to chemotherapy and has been associated with radioresistance [ 27 , 28 ].…”

Identification of Hypoxia Prognostic Signature in Glioblastoma Multiforme Based on Bulk and Single-Cell RNA-Seq

“…There are multiple studies on the construction of a LASSO prognostic model for glioblastoma. Tong et al [19] proposed a prognostic model of mitochondria and oxidative stress-related genes, whereas Zhang et al [20] built a cuproptosis-related prognostic model, which can independently predict the prognosis of GBM patients. We also created a predictive model with a similar purpose.…”

Prognostic relevance and validation of ARPC1A in the progression of low-grade glioma

“…Other mitochondrial genes such as ABCC3, HOXA4, HOXC10, NNMT, and SCNN1B are typically increased in their expression as the grade of glioma and the higher expression of these genes have been associated with poor prognosis in LGG [56]. Other mitochondrial oxidative-stress-related genes including CTSL, TXNRD2, NUDT1, STOX1, and CYP2E1 have been reported differentially expressed with potential prediction accuracy of glioma [57]. CMC1, COX20, and UQCRB are other mitochondrial genes specifically involved in the prognosis of glioma [37].…”