Common hub genes in Uremia and Kidney Renal Clear Cell Carcinoma (KIRC): their role in KIRC pathogenesis through activation of the citrate cycle pathway.

INTRODUCTION: Uremia and Kidney Renal Clear Cell Carcinoma (KIRC) are two significant health conditions that place a considerable burden on patients globally. This study aims to identify and validate common hub genes in uremia and KIRC, investigate their molecular roles, and explore their potential as biomarkers for diagnosis and prognosis. METHOD: We retrieved two publicly available datasets (GSE37171 for uremia and GSE66272 for KIRC) from the Gene Expression Omnibus (GEO) and identified differentially expressed genes (DEGs) using the limma package in R. A Venn analysis was conducted to identify shared DEGs between the two conditions. The identified genes were subjected to protein-protein interaction (PPI) network construction using the STRING database and Cytoscape software, followed by hub gene identification with the CytoHubba plugin. Hub gene expression was validated in 9 KIRC cell lines and 5 normal control kidney cell lines using RT-qPCR. Functional assays, including gene knockdown, cell proliferation, colony formation, and wound healing assays were performed. RESULTS: A total of 114 shared DEGs were identified between uremia and KIRC. ALDH18A1, CALU, DERL1, and SUCLG2 were identified as hub genes with the highest connectivity in the PPI network. These genes were significantly upregulated in KIRC cell lines compared to normal controls. Validation using the KIRC TCGA dataset confirmed their upregulation in tumor samples and across different KIRC subtypes. Further analyses revealed hypomethylation of the hub genes, along with significant mutation frequencies and CNV amplifications. High expression of these hub genes was associated with poor survival in KIRC patients, and their correlation with immune cells and drug resistance was also observed. Gene knockdown of ALDH18A1 and CALU in 786-O and Uremic-786-O significantly reduced cell proliferation, colony formation, and migration, emphasizing their role in KIRC and Uremia pathogenesis. Additionally, silencing these genes decreased the expression of PDK1 and IDH1, key activators of the Citrate cycle, suggesting their involvement in metabolic dysregulation in KIRC. CONCLUSION: This study identifies ALDH18A1, CALU, DERL1, and SUCLG2 as potential biomarkers for KIRC diagnosis and prognosis. Our findings suggest that these hub genes are involved in the dysregulation of key metabolic pathways, including the citrate cycle, and may serve as therapeutic targets in KIRC. CLINICAL TRIAL NUMBER: Not applicable.