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

Sarah P. Short, Jennifer M. Pilat, Caitlyn W. Barrett, Vishruth K. Reddy, Yael Haberman, Jared R. Hendren, Benjamin J. Marsh, Cody E. Keating, Amy K. Motley, Kristina E. Hill, Anne E. Zemper, M. Kay Washington, Chanjuan Shi, Xi Chen, Keith T. Wilson, Jeffrey S. Hyams, Lee A. Denson, Raymond F. Burk, Michael J. Rosen, Christopher S. Williams

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1694-1708.e3
JournalGastroenterology
Volume160
Issue number5
DOIs
StatePublished - Apr 2021

Keywords

  • Colitis-Associated Cancer
  • Reactive Oxygen Species
  • Selenium
  • Selenoproteins

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