Advertisement
Original Research Full Report: Basic and Translational—Alimentary Tract| Volume 160, ISSUE 5, P1694-1708.e3, April 01, 2021

Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer

  • Sarah P. Short
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee

    Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Jennifer M. Pilat
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee
    Search for articles by this author
  • Caitlyn W. Barrett
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee
    Search for articles by this author
  • Vishruth K. Reddy
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee

    Department of Radiation Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Yael Haberman
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

    Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio

    Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, Israel
    Search for articles by this author
  • Jared R. Hendren
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    School of Medicine, Southern Illinois University, Springfield, Illinois
    Search for articles by this author
  • Benjamin J. Marsh
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Cody E. Keating
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Amy K. Motley
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Kristina E. Hill
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Anne.E. Zemper
    Affiliations
    Department of Biology, University of Oregon, Eugene, Oregon

    Institute of Molecular Biology, University of Oregon, Eugene, Oregon
    Search for articles by this author
  • M. Kay Washington
    Affiliations
    Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Chanjuan Shi
    Affiliations
    Department of Pathology, Duke University School of Medicine, Durham, North Carolina
    Search for articles by this author
  • Xi Chen
    Affiliations
    Department of Public Health Sciences and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida
    Search for articles by this author
  • Keith T. Wilson
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee

    Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee

    Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee

    Vanderbilt Ingram Cancer Center, Nashville, Tennessee
    Search for articles by this author
  • Jeffrey S. Hyams
    Affiliations
    Connecticut Children's Medical Center, Hartford, Connecticut
    Search for articles by this author
  • Lee A. Denson
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

    Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
    Search for articles by this author
  • Raymond F. Burk
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee
    Search for articles by this author
  • Michael J. Rosen
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

    Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
    Search for articles by this author
  • Christopher S. Williams
    Correspondence
    Correspondence Address correspondence to: Christopher S. Williams, MD, PhD, Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, 1030 LH, 2215-B Garland Avenue, Nashville, Tennessee 37232.
    Affiliations
    Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee

    Program in Cancer Biology, Vanderbilt University, Nashville, Tennessee

    Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee

    Veterans Affairs Tennessee Valley Health Care System, Nashville, Tennessee

    Vanderbilt Ingram Cancer Center, Nashville, Tennessee
    Search for articles by this author
Published:December 31, 2020DOI:https://doi.org/10.1053/j.gastro.2020.12.059

      Background & Aims

      Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context.

      Methods

      Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples.

      Results

      Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate–mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression.

      Conclusions

      Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.

      Graphical abstract

      Keywords

      Abbreviations used in this paper:

      AOM (azoxymethane), BMDM (bone marrow–derived macrophages), CAC (colitis-associated cancer), CD (Crohn’s disease), DSS (dextran sodium sulfate), GPx (glutathione peroxidase), IBD (inflammatory bowel disease), IEC (intestinal epithelial cell), mRNA (messenger RNA), Na2SeO3 (sodium selenite), ROS (reactive oxygen species), SELENOP (selenoprotein P), UC (ulcerative colitis), WT (wild-type)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Short S.P.
        • Pilat J.M.
        • Williams C.S.
        Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease.
        Free Radic Biol Med. 2018; 127: 26-35
        • Baum M.K.
        • Shor-Posner G.
        • Lai S.
        • et al.
        High risk of HIV-related mortality is associated with selenium deficiency.
        J Acquir Immune Defic Syndr Hum Retrovirol. 1997; 15: 370-374
        • Gladyshev V.N.
        • Stadtman T.C.
        • Hatfield D.L.
        • et al.
        Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase.
        Proc Natl Acad Sci U S A. 1999; 96: 835-839
        • Beck M.A.
        • Williams-Toone D.
        • Levander O.A.
        Coxsackievirus B3-resistant mice become susceptible in Se/vitamin E deficiency.
        Free Radic Biol Med. 2003; 34: 1263-1270
        • Beck M.A.
        • Shi Q.
        • Morris V.C.
        • et al.
        Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates.
        Nat Med. 1995; 1: 433-436
        • Harthill M.
        Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases.
        Biol Trace Elem Res. 2011; 143: 1325-1336
        • Burk R.F.
        • Hill K.E.
        Regulation of selenium metabolism and transport.
        Annu Rev Nutr. 2015; 35: 109-134
        • Brigelius-Flohe R.
        • Maiorino M.
        Glutathione peroxidases.
        Biochim Biophys Acta. 2013; 1830: 3289-3303
        • Arner E.S.
        • Holmgren A.
        The thioredoxin system in cancer.
        Semin Cancer Biol. 2006; 16: 420-426
        • Eaden J.A.
        • Abrams K.R.
        • Mayberry J.F.
        The risk of colorectal cancer in ulcerative colitis: a meta-analysis.
        Gut. 2001; 48: 526-535
        • Itzkowitz S.H.
        • Yio X.
        Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation.
        Am J Physiol Gastrointest Liver Physiol. 2004; 287: G7-G17
        • Cadet J.
        • Wagner J.R.
        DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation.
        Cold Spring Harb Perspect Biol. 2013; 5
        • Kawanishi S.
        • Hiraku Y.
        • Pinlaor S.
        • et al.
        Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis.
        Biol Chem. 2006; 387: 365-372
        • Barrett C.W.
        • Singh K.
        • Motley A.K.
        • et al.
        Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis.
        PLoS One. 2013; 8e67845
        • Kaushal N.
        • Kudva A.K.
        • Patterson A.D.
        • et al.
        Crucial role of macrophage selenoproteins in experimental colitis.
        J Immunol. 2014; 193: 3683-3692
        • Kim J.H.
        • Hue J.J.
        • Kang B.S.
        • et al.
        Effects of selenium on colon carcinogenesis induced by azoxymethane and dextran sodium sulfate in mouse model with high-iron diet.
        Lab Anim Res. 2011; 27: 9-18
        • Esworthy R.S.
        • Aranda R.
        • Martin M.G.
        • et al.
        Mice with combined disruption of Gpx1 and Gpx2 genes have colitis.
        Am J Physiol Gastrointest Liver Physiol. 2001; 281: G848-G855
        • Barrett C.W.
        • Ning W.
        • Chen X.
        • et al.
        Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma.
        Cancer Res. 2013; 73: 1245-1255
        • Burk R.F.
        • Hill K.E.
        Selenoprotein P-expression, functions, and roles in mammals.
        Biochim Biophys Acta. 2009; 1790: 1441-1447
        • Burk R.F.
        • Hill K.E.
        Selenoprotein P: an extracellular protein with unique physical characteristics and a role in selenium homeostasis.
        Annu Rev Nutr. 2005; 25: 215-235
        • Barrett C.W.
        • Reddy V.K.
        • Short S.P.
        • et al.
        Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.
        J Clin Invest. 2015; 125: 2646-2660
        • Uronis J.M.
        • Muhlbauer M.
        • Herfarth H.H.
        • et al.
        Modulation of the intestinal microbiota alters colitis-associated colorectal cancer susceptibility.
        PLoS One. 2009; 4e6026
        • Miyoshi J.
        • Leone V.
        • Nobutani K.
        • et al.
        Minimizing confounders and increasing data quality in murine models for studies of the gut microbiome.
        Peer J. 2018; 6: e5166
        • Haberman Y.
        • Karns R.
        • Dexheimer P.J.
        • et al.
        Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response.
        Nat Commun. 2019; 10: 38
        • Hyams J.S.
        • Davis Thomas S.
        • Gotman N.
        • et al.
        Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study.
        Lancet. 2019; 393: 1708-1720
        • Means A.L.
        • Freeman T.J.
        • Zhu J.
        • et al.
        Epithelial Smad4 deletion up-regulates inflammation and promotes inflammation-associated cancer.
        Cell Mol Gastroenterol Hepatol. 2018; 6: 257-276
        • Singh K.
        • Coburn L.A.
        • Asim M.
        • et al.
        Ornithine decarboxylase in macrophages exacerbates colitis and promotes colitis-associated colon carcinogenesis by impairing M1 immune responses.
        Cancer Res. 2018; 78: 4303-4315
        • Hill K.E.
        • Wu S.
        • Motley A.K.
        • et al.
        Production of selenoprotein P (Sepp1) by hepatocytes is central to selenium homeostasis.
        J Biol Chem. 2012; 287: 40414-40424
        • Heng T.S.
        • Painter M.W.
        Immunological Genome Project Consortium. The Immunological Genome Project: networks of gene expression in immune cells.
        Nat Immunol. 2008; 9: 1091-1094
        • Shi J.
        • Hua L.
        • Harmer D.
        • et al.
        Cre driver mice targeting macrophages.
        Methods Mol Biol. 2018; 1784: 263-275
        • Carlson B.A.
        • Yoo M.H.
        • Sano Y.
        • et al.
        Selenoproteins regulate macrophage invasiveness and extracellular matrix-related gene expression.
        BMC Immunol. 2009; 10: 57
        • Barrett C.W.
        • Short S.P.
        • Williams C.S.
        Selenoproteins and oxidative stress-induced inflammatory tumorigenesis in the gut.
        Cell Mol Life Sci. 2017; 74: 607-616
        • Schaum N.
        • Karkanias J.
        • Neff N.F.
        • et al.
        Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris.
        Nature. 2018; 562: 367-372
        • Li Z.
        • Yang J.
        • Huang H.
        Oxidative stress induces H2AX phosphorylation in human spermatozoa.
        FEBS Lett. 2006; 580: 6161-6168
        • Zhao H.
        • Traganos F.
        • Albino A.P.
        • et al.
        Oxidative stress induces cell cycle-dependent Mre11 recruitment, ATM and Chk2 activation and histone H2AX phosphorylation.
        Cell Cycle. 2008; 7: 1490-1495
        • Sharma A.
        • Singh K.
        • Almasan A.
        Histone H2AX phosphorylation: a marker for DNA damage.
        Methods Mol Biol. 2012; 920: 613-626
        • Andoh A.
        • Hirashima M.
        • Maeda H.
        • et al.
        Serum selenoprotein-P levels in patients with inflammatory bowel disease.
        Nutrition. 2005; 21: 574-579
        • Xia Y.
        • Hill K.E.
        • Li P.
        • et al.
        Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects.
        Am J Clin Nutr. 2010; 92: 525-531
        • Barros S.E.L.
        • Dias T.
        • Moura M.S.B.
        • et al.
        Relationship between selenium status and biomarkers of oxidative stress in Crohn disease.
        Nutrition. 2020; 74: 110762
        • Martitz J.
        • Becker N.P.
        • Renko K.
        • et al.
        Gene-specific regulation of hepatic selenoprotein expression by interleukin-6.
        Metallomics. 2015; 7: 1515-1521
        • Bosschaerts T.
        • Guilliams M.
        • Noel W.
        • et al.
        Alternatively activated myeloid cells limit pathogenicity associated with African trypanosomiasis through the IL-10 inducible gene selenoprotein P.
        J Immunol. 2008; 180: 6168-6175
        • Dreher I.
        • Jakobs T.C.
        • Kohrle J.
        Cloning and characterization of the human selenoprotein P promoter. Response of selenoprotein P expression to cytokines in liver cells.
        J Biol Chem. 1997; 272: 29364-29371
        • Huang Z.
        • Rose A.H.
        • Hoffmann P.R.
        The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities.
        Antioxid Redox Signal. 2012; 16: 705-743
        • Virag L.
        • Jaen R.I.
        • Regdon Z.
        • et al.
        Self-defense of macrophages against oxidative injury: fighting for their own survival.
        Redox Biol. 2019; 26: 101261
        • Sosa V.
        • Moline T.
        • Somoza R.
        • et al.
        Oxidative stress and cancer: an overview.
        Ageing Res Rev. 2013; 12: 376-390
        • Hill K.E.
        • Xia Y.
        • Akesson B.
        • et al.
        Selenoprotein P concentration in plasma is an index of selenium status in selenium-deficient and selenium-supplemented Chinese subjects.
        J Nutr. 1996; 126: 138-145

      Supplementary References

        • Clausen B.E.
        • Burkhardt C.
        • Reith W.
        • et al.
        Conditional gene targeting in macrophages and granulocytes using LysMcre mice.
        Transgenic Res. 1999; 8: 265-277
        • el Marjou F.
        • Janssen K.P.
        • Chang B.H.
        • et al.
        Tissue-specific and inducible Cre-mediated recombination in the gut epithelium.
        Genesis. 2004; 39: 186-193
        • Choksi Y.A.
        • Reddy V.K.
        • Singh K.
        • et al.
        BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.
        Mucosal Immunol. 2018; 11: 1363-1374
        • Short S.P.
        • Thompson J.J.
        • Bilotta A.J.
        • et al.
        Serine threonine kinase 17A maintains the epithelial state in colorectal cancer cells.
        Mol Cancer Res. 2019; 17: 882-894
        • Short S.P.
        • Kondo J.
        • Smalley-Freed W.G.
        • et al.
        p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia.
        J Clin Invest. 2017; 127: 4462-4476
        • Sheehan T.M.
        • Gao M.
        Simplified fluorometric assay of total selenium in plasma and urine.
        Clin Chem. 1990; 36: 2124-2126
        • Burk R.F.
        • Hill K.E.
        • Motley A.K.
        • et al.
        Deletion of selenoprotein P upregulates urinary selenium excretion and depresses whole-body selenium content.
        Biochim Biophys Acta. 2006; 1760: 1789-1793
        • Lawrence R.A.
        • Burk R.F.
        Glutathione peroxidase activity in selenium-deficient rat liver. 1976.
        Biochem Biophys Res Commun. 2012; 425: 503-509
        • Read R.
        • Bellew T.
        • Yang J.G.
        • et al.
        Selenium and amino acid composition of selenoprotein P, the major selenoprotein in rat serum.
        J Biol Chem. 1990; 265: 17899-17905
        • Hill K.E.
        • Zhou J.
        • Austin L.M.
        • et al.
        The selenium-rich C-terminal domain of mouse selenoprotein P is necessary for the supply of selenium to brain and testis but not for the maintenance of whole body selenium.
        J Biol Chem. 2007; 282: 10972-10980
        • Burk R.F.
        • Norsworthy B.K.
        • Hill K.E.
        • et al.
        Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial.
        Cancer Epidemiol Biomarkers Prev. 2006; 15: 804-810
        • Short S.P.
        • Barrett C.W.
        • Stengel K.R.
        • et al.
        Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma.
        Oncogene. 2019; 38: 5091-5106
        • Florian S.
        • Krehl S.
        • Loewinger M.
        • et al.
        Loss of GPx2 increases apoptosis, mitosis, and GPx1 expression in the intestine of mice.
        Free Radic Biol Med. 2010; 49: 1694-1702
        • Burk R.F.
        • Hill K.E.
        • Motley A.K.
        • et al.
        Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration.
        FASEB J. 2014; 28: 3579-3588