Oxidative Phosphorylation-Related Signature Participates in Cancer Development, and PTPRG Overexpression Suppresses the Cancer Progression in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) was a common cancer type diagnosed with frequent metastases, harboring an unfavorable therapeutic response, and results in a poor prognosis. More promising therapeutic targets are urgently required for treating ccRCC. This study was conducted to explore the role of oxidative phosphorylation in ccRCC development and reveal its clinical potential. We first identified oxidative phosphorylation-related clusters based on consensus clustering and validated their diversity in the genome instability, environmental infiltration, and immunosuppression by Gistic, ESTIMATE, GSVA, and TIDE web tools. We also compared their prognostic and clinical feature differences and predicted the IC50 level between the clusters using pRRophetic. Subsequently, we performed weighted gene coexpression network analysis to select cluster-related genes and performed functional analysis for them. The cluster-related genes were adopted to construct a risk score and nomogram for predicting patient prognosis with predictive accuracy evaluated. Finally, we performed lentivirus to induce ccRCC cell PTPRG overexpression and conducted western blot experiments to detect the critical protein expression of oxidative phosphorylation, apoptosis, cell cycle, and epithelial-mesenchymal transition processes. Also, the cell cycle and apoptosis level were evaluated by flow cytometry. As a result, we discovered that both the C1 cluster and high-risk group predicted patient survival with high accuracy and characterized lower survival rates, lower oxidative phosphorylation levels, higher immune infiltration, and malignant clinical features. Besides, we observed that overexpression of PTPRG activated oxidative phosphorylation and inhibited apoptosis. Its overexpression also depressed the epithelial-mesenchymal transition and promoted G1/S cell cycle arrest. Comprehensively, we confirmed the anticancer role of oxidative phosphorylation in ccRCC cells and discovered its association with immune and immunosuppression. PTPRG was also identified as a potential therapeutic target due to its multiple anticancer effects. We believe this study discovered a novel mechanism of ccRCC pathological progression and will provide promising targets for therapeutic strategy development.