Selenium is a necessary trace element that is incorporated as selenocysteine into selenoproteins, such Selenoprotein P (SEPP1). Several epidemiological studies have inversely correlated nutritional selenium status and cancer risk, particularly in colon cancer. Because SEPP1 is the only selenoprotein to contain more than one selenocysteine, SEPP1 is hypothesized to supply various tissues with selenium to allow in situ generation of selenium containing proteins. However, SEPP1 also contains a redox domain and fulfills a generalized antioxidant function. Such activities suggest that SEPP1 could play a significant role in cancer prevention, and indeed SEPP1 message is downregulated in colorectal cancers. Furthermore, we have found that global SEPP1 reduction increases tumorigenesis in mice placed on a colitis associated carcinoma protocol. But how is SEPP1 mediating these changes in tumor formation? As the majority of SEPP1 is thought to be synthesized in the liver, we previously generated a liver- specific Sepp1 knock-out mouse. Surprisingly, loss of SEPP1 in the liver had no effect on colitis score or tumor formation, suggesting a local source of SEPP1 might modify or influence tumorigenesis. Two possible sources for this locally-derived SEPP1 include 1) intestinal epithelial cells and 2) infiltrating immune cells. Both cell types are known o produce SEPP1, but their separate contributions to inflammatory injury and cancer are yet unknown. Therefore, we will delete SEPP1 in both cell populations individually to define tissue-specific contributions of SEPP1 to inflammatory carcinogenesis. To determine how SEPP1 influences tumor formation, we will utilize a combination of in vivo and ex vivo approaches for both epithelial and myeloid cell populations. Using mouse models of colitis and dysplasia, intestinal enteroid and macrophage/enteroid co-culture, and bone marrow macrophage culture we will determine how tissue-specific SEPP1 affects intestinal homeostasis, intestinal injury, oxidative stress, and macrophage function, and how each function contributes to colitis and associated dysplasia. Interestingly, we have found that Sepp1 loss increases oxidative damage in ex vivo intestinal culture models, and colitis- associated carcinoma is characterized by increased oxidant stress. To specifically investigate the role of oxidative damage and its mechanistic contribution to the SEPP1 phenotype, we will utilize the compound salicylamine, an inhibitor of oxidative adducts, as well as redox-deficient SEPP1 variants. Together, these experiments will elucidate the roles of selenium and SEPP1 in colon disease and disease progression.

Public Health Relevance

Selenium supplementation has been associated with decreased cancer risk, and we have shown that reduction of selenium-containing proteins, such as Selenoprotein P (SEPP1), increases intestinal injury and tumor formation. The studies proposed here will investigate how SEPP1 influences tumorigenesis by analyzing the effect of SEPP1 loss in specific cell types important for inflammatory injury and cancer. These studies will also determine what function(s) of SEPP1 protect cells from damage

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Densmore, Christine L
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Vanderbilt University Medical Center
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Choksi, Yash A; Reddy, Vishruth K; Singh, Kshipra et al. (2018) BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability. Mucosal Immunol 11:1363-1374
Short, Sarah P; Pilat, Jennifer M; Williams, Christopher S (2018) Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease. Free Radic Biol Med 127:26-35
Short, Sarah P; Costacurta, Patricia W; Williams, Christopher S (2017) Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer. Curr Colorectal Cancer Rep 13:183-191
McDonough, Elizabeth M; Barrett, Caitlyn W; Parang, Bobak et al. (2017) MTG16 is a tumor suppressor in colitis-associated carcinoma. JCI Insight 2:
Barrett, Caitlyn W; Short, Sarah P; Williams, Christopher S (2017) Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut. Cell Mol Life Sci 74:607-616
Short, Sarah P; Williams, Christopher S (2017) Selenoproteins in Tumorigenesis and Cancer Progression. Adv Cancer Res 136:49-83
Short, Sarah P; Whitten-Barrett, Caitlyn; Williams, Christopher S (2016) Selenoprotein P in colitis-associated carcinoma. Mol Cell Oncol 3:e1075094