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ResearchIn-Press PreviewGastroenterology Open Access | 10.1172/JCI165988

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions

Jennifer M. Pilat,1 Rachel E. Brown,1 Zhengyi Chen,2 Nathaniel J. Berle,3 Adrian P. Othon,3 M. Washington,4 Shruti A. Anant,5 Suguru Kurokawa,6 Victoria H. Ng,1 Joshua J. Thompson,1 Justin Jacobse,3 Jeremy A. Goettel,4 Ethan Lee,7 Yash A. Choksi,3 Ken S. Lau,8 Sarah P. Short,3 and Christopher S. Williams3

1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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1Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, United States of America

2Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, United States of America

3Department of Medicine, Vanderbilt University Medical Center, Nashville, United States of America

4Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, United States of America

5Department of Medicine, Health, and Society, Vanderbilt University, Nashville, United States of America

6Department of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan

7Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, United States of America

8Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States of America

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Published May 11, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI165988.
Copyright © 2023, Pilat et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 11, 2023 - Version history
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Abstract

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic colorectal carcinogenesis. In human scRNA-seq datasets, we discovered that SELENOP expression rises as normal colon stem cells transform into adenomas that progress into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involves conditional, intestinal epithelial-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as CRC and noncancer cell lines. Selenop KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining SELENOP’s mechanism of action, we mapped protein-protein interactions between SELENOP and the WNT co-receptor low-density lipoprotein receptor-related protein 5/6 (LRP5/6). Lastly, we confirmed that SELENOP:LRP5/6 interactions contributed to SELENOP’s effects on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.

Graphical Abstract
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