Protein-Protein Interactions in Papillary and Nonpapillary Urothelial Carcinoma Architectures: Comparative Study.

Abstract

Background: Bladder cancer is a disease characterized by complex perturbations in gene networks and is heterogeneous in terms of histology, mutations, and prognosis. Advances in high-throughput sequencing technologies, genome-wide association studies, and bioinformatics methods have revealed greater insights into the pathogenesis of complex diseases. Network biology-based approaches have been used to identify complex protein-protein interactions (PPIs) that can lead to potential drug targets. There is a need to better understand PPIs specific to urothelial carcinoma.

Objective: This study aimed to elucidate PPIs specific to papillary and nonpapillary urothelial carcinoma and identify the most connected or "hub" proteins, as these are potential drug targets.

Methods: A novel PPI analysis tool, Proteinarium, was used to analyze RNA sequencing data from 132 patients with papillary and 270 patients with nonpapillary urothelial carcinoma from the TCGA Cell 2017 dataset and 39 patients with papillary and 88 patients with nonpapillary urothelial carcinoma from the TCGA Nature 2014 dataset. Hub proteins were identified in distinct PPI networks specific to papillary and nonpapillary urothelial carcinoma. Statistical significance of clusters was assessed using the Fisher exact test (P<.001), and network separation was quantified using the interactome-based separation score.

Results: RPS27A, UBA52, and VAMP8 were the most connected or "hub" proteins identified in the network specific to the papillary urothelial carcinoma. In the network specific to the nonpapillary carcinoma, GNB1, RHOA, UBC, and FPR2 were found to be the hub proteins. Notably, GNB1 and FPR2 were among the proteins that have existing drugs targeting them.

Conclusions: We identified distinct PPI networks and the hub proteins specific to papillary and nonpapillary urothelial carcinomas. However, these findings are limited by the use of transcriptomic data and require experimental validation to confirm the functional relevance of the identified targets.