A Comprehensive Bioinformatics Analysis of Notch Pathways in Bladder Cancer

SIMPLE SUMMARY: The Notch pathway is important in embryology and numerous tumor diseases. However, its role in bladder cancer (BCa) has not been deeply investigated thus far. Gene expression data are available for BCa, and bioinformatics analysis can provide insights into a possible role of the Notch pathway in BCa development and prognosis. Using this information can help in better understanding the origin of BCa, finding novel biomarkers for prediction of disease progression, and potentially opening new avenues to improved treatment. Our analysis identified the Notch receptors NOTCH2/3 and their ligand DLL4 as potential drivers of BCa by direct interaction with basic cell functions and indirect by modulating the immune response. ABSTRACT: Background: A hallmark of Notch signaling is its variable role in tumor biology, ranging from tumor-suppressive to oncogenic effects. Until now, the mechanisms and functions of Notch pathways in bladder cancer (BCa) are still unclear. Methods: We used publicly available data from the GTEx and TCGA-BLCA databases to explore the role of the canonical Notch pathways in BCa on the basis of the RNA expression levels of Notch receptors, ligands, and downstream genes. For statistical analyses of cancer and non-cancerous samples, we used R software packages and public databases/webservers. Results: We found differential expression between control and BCa samples for all Notch receptors (NOTCH1, 2, 3, 4), the delta-like Notch ligands (DLL1, 3, 4), and the typical downstream gene hairy and enhancer of split 1 (HES1). NOTCH2/3 and DLL4 can significantly differentiate non-cancerous samples from cancers and were broadly altered in subgroups. High expression levels of NOTCH2/3 receptors correlated with worse overall survival (OS) and shorter disease-free survival (DFS). However, at long-term (>8 years) follow-up, NOTCH2 expression was associated with a better OS and DFS. Furthermore, the cases with the high levels of DLL4 were associated with worse OS but improved DFS. Pathway network analysis revealed that NOTCH2/3 in particular correlated with cell cycle, epithelial–mesenchymal transition (EMT), numbers of lymphocyte subtypes, and modulation of the immune system. Conclusions: NOTCH2/3 and DLL4 are potential drivers of Notch signaling in BCa, indicating that Notch and associated pathways play an essential role in the progression and prognosis of BCa through directly modulating immune cells or through interaction with cell cycle and EMT.