# Defining the role of intestinal epithelial selenoprotein P (SEPP1) in sporadic colorectal carcinogenesis

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2021 · $30,396

## Abstract

Project Summary/Abstract
Despite advances in treatment and screening, colorectal cancer (CRC) remains the third most common cancer
and fourth most common cause of cancer-related death worldwide. Although the role of selenium (Se) in cancer
remains controversial, several epidemiological studies have revealed inverse correlations between CRC risk and
Se nutritional levels. Additional molecular studies have demonstrated that Se deficiency worsens inflammatory-
driven colitis-associated cancer (CAC) and stimulates the Wnt signaling pathway, which is inappropriately
activated in the vast majority of CRCs. Se is an essential trace element incorporated into selenoproteins (SEPs)
as selenocysteine (SEC). As both the most highly expressed SEP and the only SEP with multiple SECs, SEPP1
is hypothesized to supply Se to various tissues for production of the other 24 SEPs in the genome. In addition to
its Se transport capability, SEPP1 possesses antioxidant activity via its redox domain. Collectively, such
functions purport a cancer-preventive role for SEPP1. In fact, SEPP1 mRNA expression is downregulated in
CRCs. Moreover, global SEPP1 reduction promoted tumorigenesis and activated Wnt signaling in a CAC animal
model. SEPP1 is primarily synthesized in the liver and delivered to distant tissues through the plasma.
Surprisingly, we observed that liver-specific Sepp1 deletion did not impact colitis severity nor subsequent
tumorigenesis in a murine CAC model. These results suggest a protective role for locally-produced SEPP1.
Interestingly, Sepp1 deletion specifically from the intestinal epithelium phenocopied global SEPP1 reduction and
decreased tumorigenesis in the same CAC model. Moreover, dietary Se supplementation attenuated
tumorigenesis and promoted survival in Sepp1-deficient mice. While these results imply that Se and SEPP1
modify inflammatory-driven CAC, little is known about the role of epithelial SEPP1 in non-inflammatory-driven
(and much more prevalent) sporadic CRC and, importantly, if dietary Se can compensate for genetic SEP
deficiencies to protect against tumorigenesis.
To determine how SEPP1 modulates non-inflammatory-driven sporadic CRC, I will investigate the impact of
SEPP1 on initial tumor formation as well as on established colorectal tumor growth. Specifically, I will analyze
the effects of intestinal epithelial SEPP1 loss on tumorigenesis and Wnt signaling under deficient, sufficient, and
supranutritional Se levels. Additionally, I will delineate the contributions of tumor- and host-derived SEPP1 to
established colorectal tumor growth. Lastly, I will examine the consequences of SEPP1 expression on apoptosis,
DNA damage, in vivo growth, oxidative stress, proliferation, and Wnt activation using ex vivo 3D-organoid
cultures of human primary CRC. Together, these experiments will help elucidate the roles of Se and SEPP1 in
sporadic colorectal carcinogenesis.

## Key facts

- **NIH application ID:** 10085574
- **Project number:** 5F31CA232272-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Jennifer Marie Pilat
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,396
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085574

## Citation

> US National Institutes of Health, RePORTER application 10085574, Defining the role of intestinal epithelial selenoprotein P (SEPP1) in sporadic colorectal carcinogenesis (5F31CA232272-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085574. Licensed CC0.

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