Dietary Selenium Deficiency Exacerbates DSS-Induced Epithelial Injury and AOM/DSS-Induced Tumorigenesis

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.

Crucial Role of Macrophage Selenoproteins in Experimental Colitis

“…Clinical studies have shown supplementation with Se in UC patients leads to symptomatic relief from active colitis (2–4). Furthermore, our studies demonstrating the need for selenoproteins to alleviate DSS-colitis are in agreement with a recent study demonstrating that decreased levels of dietary Se exacerbate DSS-colitis (5). More importantly, our studies implicate macrophage selenoproteins to be critical in resolution of injury.…”

“…Particularly in inflammatory bowel disease (IBD), decreased levels of Se are seen in IBD patients of ulcerative colitis (UC) or Crohn’s disease (2–4). Recent studies using a two-stage carcinogenesis model in mice demonstrated Se deficiency to exacerbate disease severity and colon cancer risk by enhanced epithelial injury (5). Previous studies from our laboratory have shown that Se through its incorporation into selenoproteins suppressed inflammation and decreased the production of tumor necrosis factor-α (TNFα) and prostaglandin E 2 (PGE 2 ) (6), which have also been shown to be elevated in the plasma of UC patients (7).…”

Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage

“…We found that SEPP1 truncation resulted in an increase in tumor number (7.9 ± 1.4 vs. 3.9 ± 0.7 tumors per mouse, P = 0.02; Figure 5B). We have previously determined that selenium deficiency results in increased dysplasia grade in this model (16). Similarly, tumor grade was more advanced in Sepp1 Δ240-361/Δ240-361 mice (P < 0.05; Figure 5C).…”

“…Several epidemiological studies have inversely correlated nutritional selenium status and cancer risk, particularly in colon cancer (15). Recently, our laboratory has demonstrated that selenium deficiency in mice exacerbates intestinal injury in response to chemical models of colitis and increases tumorigenesis in CAC modeling (16).…”

Selenoprotein P in colitis-associated carcinoma

“…[1][2][3] Indeed, previous studies from our laboratory have demonstrated that dietary selenium influences the severity of colitis and colitisassociated cancer (CAC) in mouse models. 4 The most abundant plasma selenoprotein is selenoprotein P (SEPP1). SEPP1 contains 10 selenocysteine residues and is essential for selenium transport and the production of other selenoproteins throughout the body.…”