Pan-Cancer Analysis Shows TP53 Mutations Modulate the Association of NOX4 with Genetic Programs of Cancer Progression and Clinical Outcome.

Wei Feng Ma,Thomas L Leto,Howard E Boudreau

doi:10.3390/antiox10020235

Wei Feng Ma, Thomas L Leto + Show 1 more

Open Access

https://doi.org/10.3390/antiox10020235

Copy DOI

Abstract

Previously, we have shown TGF-β-induced NOX4 expression is involved in the epithelial-to-mesenchymal transition (EMT), a process critical for cancer metastasis, and that wild-type (WT) and mutant (Mut) p53 have divergent effects on TGF-β induction of NOX4: WT-p53 suppresses whereas Mut-p53 augments NOX4 mRNA and protein production in several tumor cell models. We sought to validate and extend our model by analyzing whole-exome data of primary tumor samples in The Cancer Genome Atlas (TCGA). We constructed a Pan-Cancer dataset from 23 tumor types and explored NOX4 expression patterns in relation to EMT and patient survival. NOX4 mRNA levels increase as a function of cancer progression in several cancers and correlate with Mut-p53 mRNA and genes involved in programs of EMT, cellular adhesion, migration, and angiogenesis. Tumor macrophages appear to be a source of NOX2, whose association with genetic programs of cancer progression emulate that of NOX4. Notably, increased NOX4 expression is linked to poorer survival in patients with Mut-TP53, but better survival in patients with WT-TP53. NOX4 is negatively associated with markers of apoptosis and positively with markers of proliferation in patients with Mut-TP53, consistent with their poorer survival. These findings suggest that TP53 mutations could “switch” NOX4 from being protective and an indicator of good prognosis to deleterious by promoting programs favoring cancer progression.

Highlights

The epithelial-to-mesenchymal transition (EMT) is an important developmental program in which epithelial cells lose their polarity and tight junctions and rearrange their cytoskeleton to promote cell migration [1,2,3]
We found evidence that suggests NOX4 plays a role in several genetic programs of cancer progression including EMT, cell migration and motility, extracellular matrix (ECM) adhesion and angiogenesis, and these relationships are differentially modulated by WT and Mut-p53
We discovered a striking association between NOX2 and macrophage signatures that strongly suggests that the major source of NOX2 is derived from tumor-associated macrophages (TAMs) (Figure 5)

Summary

Introduction

The epithelial-to-mesenchymal transition (EMT) is an important developmental program in which epithelial cells lose their polarity and tight junctions and rearrange their cytoskeleton to promote cell migration [1,2,3]. Critical in normal development and wound healing, aberrant EMT has been linked to cancer metastasis, and over-expression of EMT drivers, such as SNAI1 and SNAI2, are associated with poor clinical prognoses in cancer [4,5]. The NADPH oxidase (NOX) family of enzymes are generators of reactive oxygen species (ROS) such as the superoxide anion and hydrogen peroxide. We and others have demonstrated that transforming growth factor beta (TGF-β)-induced ROS generated by NOX4 promote EMT, cell migration and invasion in different cell culture models [10,11,12,13,14,15]. Our previous work indicated that while wild-type tumor suppressor protein 53 (p53) suppresses

Methods

Results

Discussion

Conclusion