Hypoxia-Mediated Upregulation of Xanthine Oxidoreductase Causes DNA Damage of Colonic Epithelial Cells in Colitis

In this study, we investigated the role of XOR in ulcerative colitis (UC) and attempted to identify the underlying mechanisms. We used the dextran  sulfate sodium (DSS)–induced mouse model to mimic UC and observed that XOR inhibitors, allopurinol and diphenyleneiodonium sulfate (DPI), significantly alleviated UC in mice. In addition, treatment with cobalt chloride (CoCl2) and 1% O2 increased the expression of XOR and induced DNA oxidative damage in colonic epithelial cells. Furthermore, we identified that XOR accumulation in the nucleus may directly cause DNA oxidative damage and regulates HIF1 α protein levels. In addition, allopurinol effectively protected colon epithelial cells from CoCl2-induced DNA damage. Altogether, our data provided evidence that XOR could induce DNA damage under hypoxic conditions, indicating a significant role of XOR in the initiation and early development of colitis-associated colorectal cancer (CAC).
Source: Inflammation - Category: Allergy & Immunology Source Type: research