| Summary: | 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 <i>NOX4</i> 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 <i>NOX4</i> expression is linked to poorer survival in patients with Mut-<i>TP53</i>, but better survival in patients with WT-<i>TP53</i>. NOX4 is negatively associated with markers of apoptosis and positively with markers of proliferation in patients with Mut-<i>TP53</i>, consistent with their poorer survival. These findings suggest that <i>TP53</i> mutations could “switch” NOX4 from being protective and an indicator of good prognosis to deleterious by promoting programs favoring cancer progression.
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