Comprehensive Gene Expression Analyses Of Immunohistochemically Defined Subgroups Of Muscle-Invasive Urinary Bladder Urothelial Carcinoma

A number of urinary bladder urothelial carcinoma (UB UC) mRNA-based classification systems have been reported. It also has been observed that treatment response and prognosis are different for each molecular subtype. In this study, cytokeratin (CK)5/6 and CK20 immunohistochemistry (IHC) were performed, and IHC-based subgroup classification was applied. UB UC was classified into CK5/6 single-positive (SP), CK20 SP, double-positive (DP) and double-negative (DN) subgroups, and transcriptional analysis was performed. The results of gene ontology (GO) terms and functional analysis using differentially expressed genes indicate that, CK5/6 SP and DP subgroups were enriched in cell migration, immune activation, interleukin 6-Janus kinase-signal transducer and activator of transcription 3 (IL6-JAK-STAT3) signaling pathway and tumor necrosis factor-alpha signaling via the nuclear factor-kappa B (NF-kappa B) signaling pathway signature gene. In addition, compared with the other subgroups, the DN subgroup showed inhibited cell movement, cell migration, and cell activation. Furthermore, in survival analysis, the CK5/6 SP subgroup was significantly associated with poor progression-free survival (p = 0.008). The results of our study indicate that the CK5/6 positive subgroup exhibited high gene expression signature related to aggressive behavior and exhibited worse clinical outcome.