Original ResearchFull Report: Basic and Translational—Alimentary TractColonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer
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Section snippets
Murine Inflammatory Carcinogenesis Protocol
Both male and female cohoused littermate mice were used for all experiments. To minimize differences in gut microbiota, which can contribute to inflammatory tumor development, soiled bedding was collected from all cages, mixed, and redispersed 2 weeks before ΔMye and ΔIEC experiments and repeated every 2 weeks throughout the duration of the studies.22,23 After selenium supplementation, cohorts of 20- to 22-week-old liver-specific (n = 16 wild-type [WT], 17 ΔHep), myeloid-specific (n = 23 WT, 25
Hepatic Selenoprotein P Is Dispensable in Colon Inflammatory Tumorigenesis
Hepatocytes produce approximately 90% of plasma SELENOP and liver-specific Selenop deletion greatly disrupts whole-body selenium metabolism.28 Therefore, we hypothesized that loss of liver SELENOP would be the primary driver of inflammatory tumorigenesis phenotypes induced by global Selenop reduction. To test this, Selenop was deleted from the liver by crossing Selenop floxed mice with the albumin-cre driver to yield WT (Selenop+/+; alb-cre) and ΔHep (Selenopf/f; alb-cre) cohorts. Mice were
Discussion
SELENOP is a key antioxidant protein that helps maintain antioxidant defenses by both providing selenium for the translation of other antioxidant selenoproteins and catalyzing redox reactions.20 Previously, we determined that global reductions in Selenop increased inflammatory tumor formation in the AOM/DSS model.21 However, as SELENOP is a secreted protein and expressed in several different cell types, these results did not indicate which cells produce SELENOP and/or respond to SELENOP
Acknowledgments
The authors thank all members of the Williams and collaborating laboratories for thoughtful discussions about this research project. The authors would also like to thank the Vanderbilt Translational Pathology Shared Resource for aid with histology and the Cooperative Human Tissue Network for tissue procurement.
CRediT Authorship Contributions
Sarah P. Short, PhD (Conceptualization: Equal; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Writing – original draft: Lead; Writing – review &
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2023, Archives of Biochemistry and BiophysicsCitation Excerpt :In contrast to the GPX and TXNRD families of selenoproteins, the expression of “SELENO” proteins have not been thoroughly examined across several cancer types. However, low levels of the selenium carrier protein SELENOP have been associated with worse breast cancer clinical outcome and SELENOP levels have been shown to have possible diagnostic utility as a biomarker in hepatocellular carcinoma [15,16]. The Cancer Genome Atlas (TCGA) program as well as many new platforms for data mining and analysis, brought a multitude of in-silico data sets whose examination might provide insight into the pathogenesis of ccRCC as well as aid in risk stratification.
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Conflicts of interest The authors disclose no conflicts.
Funding Financial support includes National Institutes of Health (R01DK099204 to C.S. Williams, R01AT004821 and P30DK058404 to K.T. Wilson, 1F31CA167920 to C.W. Barrett, K01DK123495 and F32DK108492 to S.P. Short, F30DK103498 to V.K. Reddy, F31CA232272 to J.M. Pilat, R01DK117119 to M.J. Rosen, U01DK095745 to J.S. Hyams and L.A. Denson); Office of Medical Research, Department of Veterans Affairs (1I01BX001426 to C.S. Williams and 1I01BX001453 to K.T. Wilson); Crohn’s and Colitis Foundation (623541 to C.S. Williams, 703003 to K.T. Wilson, and 662877 to S.P. Short); Helmsley Charitable Trust and the European Research Council (758313 to Y. Haberman).