Abstract
Human colon cancers express higher levels of NADPH oxidase 1 [NOX1] than adjacent normal epithelium. It has been suggested that reactive oxygen species [ROS] derived from NOX1 contribute to DNA damage and neoplastic transformation in the colon, particularly during chronic inflammatory stress. However, the mechanism(s) underlying increased NOX1 expression in malignant tumors or chronic inflammatory states involving the intestine are poorly characterized. We examined the effects of two pro-inflammatory cytokines, IL-4 and IL-13, on the regulation of NOX1. NOX1 expression was increased 4- to 5-fold in a time- and concentration-dependent manner by both cytokines in human colon cancer cell lines when a functional Type II IL-4 receptor was present. Increased NOX1 transcription following IL-4/IL-13 exposure was mediated by JAK1/STAT6 signaling, was associated with a ROS-related inhibition of protein tyrosine phosphatase activity, and was dependent upon activation and specific binding of GATA3 to the NOX1 promoter. NOX1-mediated ROS production increased cell cycle progression through S-phase leading to a significant increase in cellular proliferation. Evaluation of twenty pairs of surgically-resected colon cancers and their associated uninvolved adjacent colonic epithelium demonstrated a significant increase in the active form of NOX1, NOX1-L, in tumors compared to normal tissues, and a significant correlation between the expression levels of NOX1 and the Type II IL-4 receptor in tumor and the uninvolved colon. These studies imply that NOX1 expression, mediated by IL-4/IL-13, could contribute to an oxidant milieu capable of supporting the initiation or progression of colonic cancer, suggesting a role for NOX1 as a therapeutic target.
Highlights
A robust flux of reactive oxygen species [ROS] may produce significant tissue injury [1], low intracellular ROS levels, especially of H2O2, can play a critical role in signal transduction [2, 3], providing essential proliferative signals required for tumor cell growth [4] and angiogenesis [5, 6]
Western analysis revealed that increased NOX1 protein levels correlated with the increase in NOX1 mRNA produced by IL-4 exposure (Figure 1B)
In concert with these results, we found that IL-4 increased NOX1 expression in other colon cancer lines, including DLD-1, WiDr, NCI-H508, and SW403 cells (Supplementary Figure S1B)
Summary
A robust flux of reactive oxygen species [ROS] may produce significant tissue injury [1], low intracellular ROS levels, especially of H2O2, can play a critical role in signal transduction [2, 3], providing essential proliferative signals required for tumor cell growth [4] and angiogenesis [5, 6]. While NOX1 appears to contribute to gastrointestinal host defense and wound healing [18,19,20], there is evidence that premalignant, chronic inflammation of the colon (in mouse www.impactjournals.com/oncotarget models) is associated with functional expression of NOX1 [21]; NOX1 could contribute to the pathogenesis of inflammation-related colonic malignancies. These recent genetic studies are consistent with the demonstration of enhanced NOX1 expression in vitro following exposure of intestinal cancer cells to the pro-inflammatory cytokines interferon-γ [IFN-γ] and tumor necrosis factor-α [TNF-α] [22]. Despite the fact that a wide range of inflammatory cytokines has been associated with pre-malignant chronic inflammation of the colon and inflammatory bowel disease [23], gaps exist in our understanding of the regulatory mechanisms (beyond plasma membrane association or phosphorylation of components of the NOX1 complex) [24, 25] that control NOX1 expression in the colon, in response to inflammatory stimuli
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