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

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2646-2660
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Selenoprotein P
Genomic Instability
Colitis
Selenium
Carcinogenesis
Oxidative Stress
Antioxidants
Macrophages
Organoids
Selenoproteins
Haploinsufficiency
Micronutrients
Tumor Burden
Inflammatory Bowel Diseases
Malnutrition
Colonic Neoplasms
DNA Damage
Cell Survival
Stem Cells
Epithelial Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Barrett, C. W., Reddy, V. K., Short, S. P., Motley, A. K., Lintel, M. K., Bradley, A. M., ... Williams, C. S. (2015). Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. Journal of Clinical Investigation, 125(7), 2646-2660. https://doi.org/10.1172/JCI76099

Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. / Barrett, Caitlyn W.; Reddy, Vishruth K.; Short, Sarah P.; Motley, Amy K.; Lintel, Mary K.; Bradley, Amber M.; Freeman, Tanner; Vallance, Jefferson; Ning, Wei; Parang, Bobak; Poindexter, Shenika V.; Fingleton, Barbara; Chen, Xi; Washington, Mary K.; Wilson, Keith T.; Shroyer, Noah F.; Hill, Kristina E.; Burk, Raymond F.; Williams, Christopher S.

In: Journal of Clinical Investigation, Vol. 125, No. 7, 01.01.2015, p. 2646-2660.

Research output: Contribution to journalArticle

Barrett, CW, Reddy, VK, Short, SP, Motley, AK, Lintel, MK, Bradley, AM, Freeman, T, Vallance, J, Ning, W, Parang, B, Poindexter, SV, Fingleton, B, Chen, X, Washington, MK, Wilson, KT, Shroyer, NF, Hill, KE, Burk, RF & Williams, CS 2015, 'Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage', Journal of Clinical Investigation, vol. 125, no. 7, pp. 2646-2660. https://doi.org/10.1172/JCI76099
Barrett, Caitlyn W. ; Reddy, Vishruth K. ; Short, Sarah P. ; Motley, Amy K. ; Lintel, Mary K. ; Bradley, Amber M. ; Freeman, Tanner ; Vallance, Jefferson ; Ning, Wei ; Parang, Bobak ; Poindexter, Shenika V. ; Fingleton, Barbara ; Chen, Xi ; Washington, Mary K. ; Wilson, Keith T. ; Shroyer, Noah F. ; Hill, Kristina E. ; Burk, Raymond F. ; Williams, Christopher S. / Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 7. pp. 2646-2660.
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