Comprehensive Bioinformatic and miRNA-Driven Analysis of the Multimeric Canonical I Kappa B Kinase (IKK) Complex in...

Uterine corpus endometrial carcinoma (UCEC) is the most common gynecologic malignancy, and aberrant canonical NF-κB signaling is implicated in uterine corpus endometrial carcinoma (UCEC), yet the expression, epigenetic, and prognostic profile of IκB kinase (IKK) complex subunits CHUK (IKKα), IKBKB (IKKβ), and IKBKG (NEMO) remains undefined. This study assessed expression, methylation, miRNA regulation, and clinical relevance of IKK-complex genes in UCEC using public datasets. RNA-seq expression (TCGA-UCEC; GEPIA2) showed significant downregulation of IKBKB in tumors versus normal endometrium (unpaired Wilcoxon), whereas CHUK and IKBKG showed non-significant increases; immunohistochemistry (Human Protein Atlas) illustrated heterogeneity and suggested possible mRNA-protein discordance for IKBKB. Promoter methylation analysis (UALCAN; Illumina 450K) identified CHUK hypomethylation and IKBKG hypermethylation in tumors, with no significant change for IKBKB. Stratification showed IKBKB suppression across clinicopathological strata and TP53 mutant/wild-type tumors; IKBKG decreased across subtypes and stages. Pan-cancer profiling (TIMER2.0) highlighted IKBKB as the broadly dysregulated IKK member across malignancies. STRING networks indicated connectivity with NF-κB mediators (e.g., RELA, NFKB1, TRAF6). miRNA predictions (miRDB/TargetScan) revealed shared regulation (CHUK-IKBKB: 14 miRNAs; CHUK-IKBKG: 2; IKBKB-IKBKG: 0). Kaplan-Meier analysis indicated that elevated IKBKG expression correlated with reduced overall survival (HR = 1.85, p = 0.0037), while CHUK expression did not correlate with survival, and IKBKB exhibited a non-significant trend. In a multivariable Cox regression analysis, high IKBKG expression continued to show a significant association with reduced overall survival, even after adjusting for age, histological type, histological grade, and TCGA molecular subtype (adjusted HR = 1.58, 95% CI = 1.00-2.47, p = 0.048). These findings collectively suggest the potential prognostic significance of IKBKG in UCEC, although independent validation in larger, comprehensively annotated cohorts is still required. Collectively, these findings suggest IKBKG as a candidate negative prognostic marker and indicator in UCEC, warranting experimental validation.