Dysregulation of the NRF2/KEAP1 signaling pathway and its impact on the development of bladder cancer

Abstract

Aim: To perform a comparative analysis of genetic alterations in the Nuclear factor erythroid 2-related factor 2 or NFE2L2 / Kelch-like ECH-associated protein 1 (NRF2/KEAP1) pathway and to evaluate their impact on bladder cancer pathology.

Methods: DNA sequencing was performed on 40 bladder cancer patients to identify potential mutations in the KEAP1 and NRF2 genes. The pathogenic effects of the identified mutations were predicted using PolyPhen-2 and SNAP tools. Various databases were utilized to analyze mutational profiles, mRNA expression alterations, and survival outcomes, while the STRING database was employed to examine protein–protein interactions.

Results: Experimental mutation analysis detected 9 mutations in the KEAP1 and NRF2 genes. Analysis of data from the Cancer Genome Atlas (TCGA) identified a total of 31 mutations across these two genes. In patients with high-grade bladder cancer, potentially pathogenic mutations were observed in the BTB and IVR domains of KEAP1 and in the topologically associating domain (TAD) of NRF2. Expression levels of NRF2 were significantly lower in patients compared to healthy controls (p < 0.01). Protein–protein interaction analysis revealed interactions with the Cullin 3 (CUL3) splicing factor, which is a core component of the E3 ubiquitin ligase complex.

Conclusion: The findings of the present study suggest that gene mutations and expression alterations within the NRF2/KEAP1 pathway may serve as potential risk factors for the development of bladder cancer.