NFE2L3 promotes tumor progression and predicts a poor prognosis of bladder cancer

Abstract The high incidence and vulnerability to recurrence of bladder urothelial carcinoma (BLCA) is a challenge in the clinical. Recent studies have revealed that NFE2L3 plays a vital role in the carcinogenesis and progression of different human tumors. However, the role of NFE2L3 in bladder cancer has not been elucidated. In this study, NFE2L3 expression was significantly increased in bladder cancer samples. Its high expression was associated with advanced clinicopathological characteristics and was an independent prognostic factor for overall survival (OS) and metastasis-free survival (MFS) in 106 patients with BLCA. In vitro and in vivo experiments demonstrated that NFE2L3 knockdown inhibited bladder cancer cells proliferation by inducing the cell cycle arrest and cell apoptosis. Meanwhile, NFE2L3 overexpression promotes BLCA cell migration and invasion in vitro cell lines and in vivo xenografts. Moreover, we identified many genes and pathway alterations associated with tumor progression and metastasis by performing RNA-Seq analysis and functional enrichment of NFE2L3 overexpressing BLCA cells. Mechanistic investigation reveals that overexpression of NFE2L3 promoted epithelial-mesenchymal transition (EMT) in bladder cancer cells with decreased expression of gap junction-associated protein ZO-1 and epithelial marker E-cadherin with the elevation of transcription factors Snail1 and Snail2. Finally, we performed a comprehensive proteomics analysis to explore more potential molecular mechanisms. Our findings revealed that NFE2L3 might serve as a valuable clinical prognostic biomarker and therapeutic target in BLCA.