Funding Source

National Institutes of Health, Office of Medical Research, Department of Veterans Affairs, NCI Cancer Center Support Grant

Grant Number

DK080221 (CSW), R01DK82813 (RFB), P50CA095103 (MKW), R01AT004821 (KTW), R01AT004821-S1 (KTW), R01DK053620 (KTW), P01CA028842 (KTW), P01CA116087 (KTW), 1F31CA167920 (CWB), P30 DK058404, 1I01BX001426 (CSW) and 1I01BX001453 (KTW), ACS-RSG 116552 (CSW), P30CA068485

Department

Department of Biology

Document Type

Article

Publication Date

7-4-2013

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.

Comments

DOI: 10.1371/journal.pone.0067845

PubMed ID: 23861820

Funding: This work was supported by the National Institutes of Health grants DK080221 (CSW), R01DK82813 (RFB), P50CA095103 (MKW), R01AT004821 (KTW), R01AT004821-S1 (KTW), R01DK053620 (KTW), P01CA028842 (KTW), P01CA116087 (KTW), 1F31CA167920 (CWB), and P30 DK058404 (Vanderbilt Digestive Disease Research Center), Merit Review Grants from the Office of Medical Research, Department of Veterans Affairs 1I01BX001426 (CSW) and 1I01BX001453 (KTW), and ACS-RSG 116552 (CSW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was supported by an NCI T-32 Supplement T32CA009592-26. This publication was also supported in part by the NCI Cancer Center Support Grant P30CA068485 utilizing the Translational Pathology shared resource, which provided tissue processing and staining services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH

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