Multi-omics Analysis Implicates Mitochondrial Complex Assembly Protein COX18 in Mitochondrial Signaling and Tumorigenesis across Cancers.

Cytochrome c oxidase assembly protein 18 (COX18) of mitochondrial complex IV plays a vital role in mitochondrial complex assembly and function. This study explores COX18 expression across diverse cancers using TCGA, TIMER2.0, GTEx, and CPTAC databases, uncovering significant overexpression in cancers such as bladder urothelial carcinoma (BLCA), colon adenocarcinoma (COAD), and lung adenocarcinoma (LUAD); conversely, downregulation in kidney renal clear cell carcinoma (KIRC) suggests a cancer-specific role. Histochemical analysis further confirmed elevated COX18 protein in BRCA, OV, UCEC, and LUAD tumors, linking it to enhanced oncogenic metabolism. Survival analyses revealed high COX18 expression correlated with poor overall (OS) and disease-free survival (DFS) in cancers like BRCA, LUAD, and STAD, establishing its prognostic significance. Mutation analysis identified recurrent R251H mutations in colorectal adenocarcinoma, implicating COX18 in tumor progression and therapeutic resistance. Moreover, high DNA methylation levels in CESC and STAD inversely correlated with gene expression, positioning COX18 methylation as a biomarker for cancer prognosis and potential epigenetic therapies. COX18 also influenced the tumor microenvironment (TME), with upregulation correlating with increased cancer-associated fibroblast (CAF) and altered immune cell infiltration, indicating its probable role in immune modulation. Gene enrichment analysis demonstrated COX18’s involvement in mitochondrial processes, while co-expression with genes like SWSAP1 emphasized its role in mitochondrial dynamics. Additionally, gene-drug interaction studies identified Bisphenol A as a modulator of COX18 expression. This study explores the significance of COX18 as a prognostic biomarker as well as a potential therapeutic target in numerous malignancies.