title: 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.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Caitlyn W
authors.initials: CW
authors.lastname: Barrett
authors.forename: Kshipra
authors.initials: K
authors.lastname: Singh
authors.forename: Amy K
authors.initials: AK
authors.lastname: Motley
authors.forename: Mary K
authors.initials: MK
authors.lastname: Lintel
authors.forename: Elena
authors.initials: E
authors.lastname: Matafonova
authors.forename: Amber M
authors.initials: AM
authors.lastname: Bradley
authors.forename: Wei
authors.initials: W
authors.lastname: Ning
authors.forename: Shenika V
authors.initials: SV
authors.lastname: Poindexter
authors.forename: Bobak
authors.initials: B
authors.lastname: Parang
authors.forename: Vishruth K
authors.initials: VK
authors.lastname: Reddy
authors.forename: Rupesh
authors.initials: R
authors.lastname: Chaturvedi
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Fingleton
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: Sean S
authors.initials: SS
authors.lastname: Davies
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Hill
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Burk
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001397:Azoxymethane; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000737:chemistry; D016264:Dextran Sulfate; D004032:Diet; D004815:Epidermal Growth Factor / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012643:Selenium / Q000172:deficiency*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D015431:Weight Loss
chemical_list: D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016264:Dextran Sulfate; D003849:Deoxyguanosine; D012643:Selenium; D001397:Azoxymethane