Nucleocytoplasmic β‐Catenin expression contributes to neuroendocrine differentiation in muscle invasive bladder cancer

Muscle invasive bladder cancer (MIBC) is highly heterogeneous, both at the molecular level and in terms of clinical progression. Several molecular classifications have been proposed to understand this heterogeneity and contribute to diagnosis and treatment. Although the neuroendocrine-like subtype is the most aggressive and exhibits the worst survival rate when compared to other subtypes, molecular mechanisms underlying neuroendocrine differentiation have not yet been understood. The nuclear localization of β-catenin is known to be associated with the activation of the Wnt/β-catenin pathway, and it is linked to disease progression and aggressiveness in various cancer types. To decipher the mechanisms underlying the neuroendocrine differentiation of bladder cancer, we determined β-catenin expression profiles of 169 T2-stage primary MIBC samples. Immunohistochemistry analysis revealed increased expression of the most widely used NE markers SYP, CGA, and CD56 in β-catenin positive MIBC tumors. As a result of our transcriptomic analysis, we observed higher expression of neuroendocrine differentiation-related genes, and lower expression of basal differentiation and urothelial differentiation-related genes in β-catenin positive MIBC tumors. Furthermore, we applied a molecular consensus classifier to β-catenin positive and negative samples, and the NE score was significantly higher in β-catenin positive MIBC compared to others. By comparing transcriptome profiles, we reveal that β-catenin positive MIBC harbor unique gene modules and gene expression profiles that are divergent from the β-catenin negative MIBC. GO term and KEGG pathway analyses showed that various neurogenesis-related pathways as well as regulation of gene expression and chromatin remodeling were significantly enriched at β-catenin positive MIBC. Our results collectively revealed that β-catenin expression contributes to neuroendocrine differentiation of bladder cancer.