An integrated bioinformatic investigation of succinic acid metabolism related genes in ccRCC followed by preliminary validation of SLC25A4 in tumorigenesis

Abstract

Abstract The defective function of succinate dehydrogenase promotes the development and progression of kidney renal clear cell renal cell carcinoma (ccRCC). However, the molecular mechanism of succinate metabolism-related genes (SMRGs) has not been extensively studied in KIRC. First, differentially expressed SMRGs (DE-SMRGs) were screened among genesets. Next, functional enrichment analysis was performed to investigate the functions of DE-SMRGs. The univariate Cox algorithm, LASSO, and multivariate Cox analysis were performed to obtain biomarkers and build a prognostic model. Afterward, enrichment and immune microenvironment analysis were carried out in two different risk subgroups. Finally, expression validation and expression intensity of prognostic gene was verified by in situ and in vitro experiments. In total, 138 DE-SMRGs were screened by overlapping SMRGs and differentially expressed genes. The functional enrichment results revealed that DE-SMRGs were implicated in retinoic acid metabolic process and retinol metabolism. Then, 8 succinate metabolism-related biomarkers were obtained, and prognostic model was developed and SLC25A4 ranked the highest in importance. SLC25A4 was down-regulated in KIRC, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. SLC25A4 attenuated cell proliferation, cell invasion, and exerted its biological function by inhibiting the STAT3 signaling pathway. Our study reveals that succinate metabolism-related biomarkers can provide a basis for exploring the prediction of prognosis in ccRCC.

Keywords

• Clear cell renal cell carcinoma
• Succinate metabolism-related genes
• Risk score
• Prognosis