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Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage
Caitlyn W. Barrett, … , Raymond F. Burk, Christopher S. Williams
Caitlyn W. Barrett, … , Raymond F. Burk, Christopher S. Williams
Published June 8, 2015
Citation Information: J Clin Invest. 2015;125(7):2646-2660. https://doi.org/10.1172/JCI76099.
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Research Article Oncology

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

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Abstract

Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.

Authors

Caitlyn W. Barrett, Vishruth K. Reddy, Sarah P. Short, Amy K. Motley, Mary K. Lintel, Amber M. Bradley, Tanner Freeman, Jefferson Vallance, Wei Ning, Bobak Parang, Shenika V. Poindexter, Barbara Fingleton, Xi Chen, Mary K. Washington, Keith T. Wilson, Noah F. Shroyer, Kristina E. Hill, Raymond F. Burk, Christopher S. Williams

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Figure 1

Absence of SEPP1 exacerbates tumorigenesis in response to AOM and injury after chronic DSS treatment.

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Absence of SEPP1 exacerbates tumorigenesis in response to AOM and injury...
(A) Schematic of the AOM protocol used. Mice were injected with AOM and aged for 6 months before being sacrificed on day 180 after AOM treatment. (B) Schematic of the chronic DSS protocol used. Mice were subjected to three 5-day cycles of 3% DSS ad libitum. There were 16 days of recovery between each DSS administration, and mice were monitored for injury by endoscopy (black circles) 4 days after each DSS cycle (gray rectangles). (C) Immunofluorescent staining of SEPP1 (red) within the colons and small intestines of WT and Sepp1–/– mice (original magnification, ×100). (D) ACF counts per mouse in WT (n = 4), Sepp1+/– (n = 4), and Sepp1–/– (n = 3) mice subjected to the AOM protocol. (E) Endoscopic colitis score, ACF counts, and Ki67 staining in mice subjected to the chronic DSS protocol (7, WT; 10, Sepp1+/–; 10, Sepp1–/–). *P < 0.05, **P < 0.01, ***P < 0.001, 1-way ANOVA, Newman-Keuls multiple comparison test.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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