A DDX31/Mutant-p53/EGFR Axis Promotes Multistep Progression of Muscle-Invasive Bladder Cancer

Abstract

The p53 and EGFR pathways are frequently altered in bladder cancer, yet their contributions to its progression remain elusive. Here we report that DEAD box polypeptide 31 (DDX31) plays a critical role in the multistep progression of muscle-invasive bladder cancer (MIBC) through its sequential interactions with mutant p53 (mutp53) and EGFR. In early MIBC cells, nuclear DDX31-bound mutp53/SP1 enhanced mutp53 transcriptional activation, leading to migration and invasion of MIBC. Cytoplasmic DDX31 also bound EGFR and phospho-nucleolin in advanced MIBC, leading to EGFR-Akt signaling activation. High expression of both cytoplasmic DDX31 and p53 proteins correlated with poor prognosis in patients with MIBC, and blocking the DDX31/NCL interaction resulted in downregulation of EGFR/Akt signaling, eliciting an in vivo antitumor effect against bladder cancer. These findings reveal that DDX31 cooperates with mutp53 and EGFR to promote progression of MIBC, and inhibition of DDX31/NCL formation may lead to potential treatment strategies for advanced MIBC.Significance: DDX31 cooperates with mutp53 and EGFR to promote progression of muscle invasive bladder cancer. Cancer Res; 78(9); 2233-47. ©2018 AACR.