Abstract
Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis.
Highlights
The essential micronutrient selenium (Se) is of fundamental importance to human health
Animals were fed either Se-sufficient or -deficient diets for 12 weeks, an extended period of time sufficient to ensure Se deficiency which we confirmed via measurement of colonic mucosal Se levels at the end of the dextran sodium sulfate (DSS) experiment (333.1616.5 vs 60.664.1 ng/g, P,0.0001, Figure 1B) and plasma glutathione peroxidase (Gpx) activity (215.4631.6 vs 18.9627.8 nmol NADPH/ml.min, P,0.0001, Figure 1C)
Several selenoproteins have been identified as direct WNT targets [60] and Se deficiency activates WNT signaling [18], implicating Se deficiency in a proliferation pathway that is aberrantly regulated in colorectal cancer
Summary
The essential micronutrient selenium (Se) is of fundamental importance to human health. Microbial, and environmental factors have all been implicated, but the fundamental etiology remains unclear. Serum selenoprotein P (Sepp1) levels are significantly lower in patients with Crohn’s disease [6] and glutathione peroxidase 1 mRNA is significantly downregulated in mononuclear cells from patients with IBD [16]. Defects in epithelial integrity contribute to IBD pathogenesis and understanding mechanisms affecting epithelial homeostasis is a priority [17]. In this regard, Se has been directly linked to WNT signaling [18] and the intrinsic apoptosis pathway [19], suggesting that it may play a role in epithelial integrity in response to injury
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