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

doi:10.1053/j.gastro.2020.12.059

Gastroenterology

Volume 160, Issue 5, April 2021, Pages 1694-1708.e3

https://doi.org/10.1053/j.gastro.2020.12.059 Get rights and content

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

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 (Selenop^f/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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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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This retrospective study included consecutive Asian patients aged 18 to 60 years and hospitalized for CD between May 2020 and December 2020 at the Inflammatory Bowel Disease Center (Hangzhou, China). Patients with a history of extensive small intestinal surgery and/or short bowel syndrome were excluded from analysis. Serum selenium concentration was determined using inductively coupled plasma mass spectrometry. Disease severity was evaluated based on inflammatory markers (simple endoscopic score for CD, CD activity index, Harvey-Bradshaw index, serum C-reactive protein level, erythrocyte sedimentation rate, and platelet count) and markers of nutrition status (body mass index; blood hemoglobin and hematocrit; as well as serum levels of albumin, folic acid, and vitamin D). The correlations between serum selenium level and disease severity–related parameters were analyzed using univariate and multivariate analyses.
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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).

View full text

Original ResearchFull Report: Basic and Translational—Alimentary TractColonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer

Background & Aims

Methods

Results

Conclusions

Graphical abstract

Section snippets

Murine Inflammatory Carcinogenesis Protocol

Hepatic Selenoprotein P Is Dispensable in Colon Inflammatory Tumorigenesis

Discussion

Acknowledgments

CRediT Authorship Contributions

Free Radic Biol Med

Free Radic Biol Med

Biochim Biophys Acta

Semin Cancer Biol

Biochim Biophys Acta

Lancet

Cell Mol Gastroenterol Hepatol

J Biol Chem

FEBS Lett

Nutrition

Am J Clin Nutr

Nutrition

J Biol Chem

Redox Biol

Ageing Res Rev

J Nutr

High risk of HIV-related mortality is associated with selenium deficiency

J Acquir Immune Defic Syndr Hum Retrovirol

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

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates

Nat Med

Review: micronutrient selenium deficiency influences evolution of some viral infectious diseases

Biol Trace Elem Res

Regulation of selenium metabolism and transport

Annu Rev Nutr

The risk of colorectal cancer in ulcerative colitis: a meta-analysis

Gut

Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation

Am J Physiol Gastrointest Liver Physiol

Original Research
Full Report: Basic and Translational—Alimentary Tract
Colonic Epithelial-Derived Selenoprotein P Is the Source for Antioxidant-Mediated Protection in Colitis-Associated Cancer