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

Abstract

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-α signaling via the nuclear factor-κB (NF-κB) 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.

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

“…On the other hand, the lack of expression of the four markers allowed us to identify a third category, the null/DN subtype, in 8% of our cases. A similar category was also reported by Rebola et al and Kim et al using immunohistochemistry in NMIBC and MIBC, respectively [29,31,33,37,49]. A similar marker selection signature using immunohistochemistry was used to classify bladder cancer into luminal and basal categories with a high level of accuracy.…”

“…Studies have focused on developing a molecular classification potentially useful to predict prognosis and guide novel therapies in patients with bladder urothelial carcinoma to improve the current scientific knowledge of bladder cancer and provide a better framework for patient management [10,17,19,24,[27][28][29]31,33,37,42,[45][46][47][48][49][50][51][52][53][54][55][56].…”

“…Differences in methodologies and the interpretation of earlier data resulted in several molecularly defined classifications currently available [13,20,28,[31][32][33][34][35][36][37][38]. Figure 1 depicts how molecular classifications of bladder cancer have evolved over the years.…”

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation

“…Furthermore, basal tumors usually express epithelial-mesenchymal transition (EMT) markers [ 42 ], which result in neoplastic cells acquiring mesenchymal phenotypes, with increasing progression and metastatic potential [ 43 , 44 ]. In the study by Kim et al, CK5/6-positive tumors were significantly associated with lower PFS and enriched with the IL6-JAK-STAT3 and TNF-α/NF-κB signaling pathways [ 42 ], which are both significantly associated with higher aggressiveness and adverse clinical outcomes in various tumors [ 45 , 46 ]. High cell adhesion gene expression signature, especially basolateral cell adhesion-related genes, was reported by different studies [ 11 , 42 ].…”

Sulforaphane Impact on Reactive Oxygen Species (ROS) in Bladder Carcinoma

“…NF-κB signaling correlates with aggressive bladder cancer behavior and poor clinical outcome [ 138 ]. Therefore, NF-κB inhibitors have been proposed as efficacious targeted therapies [ 139 ].…”