Mitochondria-related Prognostic Molecular Markers In Glioma And Their Drug Studies

Objective: Glioma is the most common primary tumour in the central nervous system.It has a poor prognosis,a short survival period and histopathological staging does not accurately predict the prognosis of patients with glioma.The metabolic reprogramming of glioma cells increases their aggressiveness and makes them resistant to radiotherapy and resistant to chemotherapy.Since mitochondria play an important role in the metabolic reprogramming of tumour cells,we attempted to find a mitochondrial gene with immune-related characteristics to provide new ideas for the clinical diagnosis and prognosis of glioma patients.We therefore sought to identify a mitochondrial gene with an immune-related profile that could provide a new approach to the clinical diagnosis and prognosis of glioma patients,and to explore the corresponding target drugs for their treatment.Methods:(1)Genomic and clinical data of gliomas were downloaded from the The Cancer Genome Atlas(TCGA)database,and 809 mitochondria-related genes were obtained from the MITOCARTA 3.0 dataset among brain tissue.(2)Differentially expressed mitochondria-related genes were obtained by differential expression analysis.(3)Prognostic screening of differentially expressed mitochondria-related genes using univariate and multivariate regression analysis.(4)Survival analysis,ROC curves and Nomogram were used to validate the predictive effect of the model on the survival of glioma patients.(5)Univariate and multifactorial analyses of prognostic model genes and the predictiveness of column line plots(Nomogram)on survival using databases such as CGGA as an independent external dataset.(6)WB experiments on prognostic genes using glioma tissue and normal brain tissue to validate the expression of prognostic proteins.(7)Targeted drug searches were performedon prognostic genes using the cell Miner database and the potential for binding of these drugs to proteins was confirmed by molecular docking.(8)Human glioma cell lines were cultured using prognostic drugs to explore the effect on the invasive capacity of glioma cells.Results: Three mitochondria-related differential genes(ERG)(CMC1,COX20,and UQCRB)were identified as prognostic key genes for glioma and used to establish prognostic profiles,with UQCRB,CMC1 progressively increasing and COX20 progressively decreasing with decreasing risk scores.TCGA dataset model ROC curve analysis yielded areas under the curve for 1-3 year survival of 0.832,0.867,0.862.CGGA database validation and TCGA training set results were similar.A new column line graph was constructed based on 3 key genes that could predict OS for each glioma patient.and explored the prognostic model in relation to CD8+ T cells and immune checkpoints,etc.Protein levels of COX20,CMC1 and UQCRB were lower in normal brain tissue than in glioma tissue.Finally we used the cell Miner database and molecular docking to confirm that UQCRB is covalently bonded to Amonafide via lysine at position 78 and threonine at position 82,while cellular experiments suggest that Amonafide inhibits glioma migration and invasion.Conclusion:1.3 mitochondria-related genes(ERG)(CMC1,COX20,and UQCRB)were identified as having predictive value for the prognosis of patients with glioma.In this model CMC1 is the risk gene and the protective genes are COX20,and UQCRB.2.We developed a new line graph of the prognosis of glioma mitochondria based on the genes(CMC1,COX20,and UQCRB).3.We finally obtained 5 drugs through the cell Miner database that can be associated with CMC1 and UQCRB,and demonstrated through molecular docking and cellular assays that Amonafide is a promising drug for targeted glioma therapy.