Journal article
Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage
The Journal of clinical investigation, Vol.125(7), pp.2646-2660
07/01/2015
DOI: 10.1172/JCI76099
PMCID: PMC4563672
PMID: 26053663
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.
Details
- Title: Subtitle
- Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage
- Creators
- Caitlyn W. Barrett - Vanderbilt UniversityVishruth K. Reddy - Vanderbilt UniversitySarah P. Short - Vanderbilt UniversityAmy K. Motley - Vanderbilt UniversityMary K. Lintel - Vanderbilt UniversityAmber M. Bradley - Vanderbilt UniversityTanner Freeman - Vanderbilt UniversityJefferson Vallance - Cincinnati Children's Hospital Medical CenterWei Ning - Vanderbilt UniversityBobak Parang - Vanderbilt UniversityShenika V. Poindexter - Vanderbilt UniversityBarbara Fingleton - Vanderbilt UniversityXi Chen - Vanderbilt UniversityMary K. Washington - Vanderbilt UniversityKeith T. Wilson - Vanderbilt UniversityNoah F. Shroyer - Cincinnati Children's Hospital Medical CenterKristina E. Hill - Vanderbilt UniversityRaymond F. Burk - Vanderbilt UniversityChristopher S. Williams - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.125(7), pp.2646-2660
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI76099
- PMID
- 26053663
- PMCID
- PMC4563672
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 15
- Grant note
- UL1RR024975 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) T32 GM007347; R25 GM062459; T32 GM07347; T32GM07347 / NIGMS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) UL1TR000445 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) R25GM062459 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R37 ES002497 / NIEHS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) 1I01BX001426-01A1 / VA; US Department of Veterans Affairs U19 AI116497 / NIAID NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30DK058404 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01AT004821 / National Center for Complementary & Integrative Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01BX001453 / Veterans Affairs; US Department of Veterans Affairs R01AT004821-S1; R01 AT004821; R01AT004821 / NCCIH NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Complementary & Alternative Medicine P01CA116087 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) I01 BX001426; I01 BX001453 / BLRD VA R01 CA142826; P50 CA095103; P30 CA068485; P01CA116087; T32 CA009592; F31 CA167920; P50CA095103; P30CA068485; F30 CA165726; 1F31CA167920; P01CA028842; P01 CA028842; R01 CA190612; T32CA009592-26; P01 CA116087; 1F30CA165726 / NCI NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) UL1 RR024975-01; UL1 RR024975 / NCRR NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) R37ES002497 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) P30DK058404; 1F30DK096718; F30 DK096718; R01DK053620; R01 DK053620; 1F30DK103498; K08 DK080221; F30 DK103498; R01 DK099204; DK080221; P30 DK058404 / NIDDK NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) S10 OD021630 / NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA U19AI116497 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) UL1 TR000445; 2 UL1 TR000445-06 / NCATS NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Language
- English
- Date published
- 07/01/2015
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420934502771
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