116 - Divergent Effects of Wild-Type and Mutant p53 in the Induction of NOX4 during Cancer Progression: A Bioinformatics Approach

Abstract

Previously, we have shown that TGF-beta induced NADPH oxidase 4 (NOX4) expression is involved in the epithelial-to-mesenchymal transition (EMT), a process critical for cancer metastasis. Further, we found that wild-type and tumor-associated mutated forms of p53 cause divergent effects on TGF-beta induction of NOX4: wild-type (WT-p53) suppresses whereas mutant p53 (mut-p53) augments NOX4 expression in several established tumor cell models. We sought to confirm and extend our findings using publically-available sequencing data from primary tumor samples in the Cancer Genome Atlas (TCGA). Here, we report that NOX4 is differentially expressed depending on tumor type and histopathological stages. To investigate the broad significance of our previous model in many cancers, we created a pan-cancer cohort of over 23 types of primary tumors. NOX4 strongly correlates with EMT gene signatures relative to other isoforms in the NOX family in this pan-cancer cohort. We found that the strength of correlation is dependent on specific p53 hot-spot mutations. Interestingly, increased NOX4 expression is associated with poor survival outcome in patients with mut-p53, whereas increased NOX4 is correlated with better survival in patients with WT-p53. We uncovered other divergent effects of p53 mutation status on apoptosis and proliferation marker mRNA levels as a function of NOX4 that may further support roles for NOX4 in cancer progression.