A selenium transport protein produced in the colon is underexpressed in patients with ulcerative colitis and helps protect against colitis-associated cancer in an animal model, Vanderbilt investigators have discovered.
The findings, reported in the journal Gastroenterology, suggest that colon-produced selenoprotein P may be a novel biomarker for assessing disease severity and cancer risk in patients with inflammatory bowel disease (IBD).
IBD is characterized by chronic inflammation of the gastrointestinal tract and includes the conditions Crohn’s disease and ulcerative colitis. Patients with IBD are at increased risk for developing colitis-associated cancer, and the risk climbs with more severe and long-lasting disease.
IBD also reduces absorption of key nutrients, including the micronutrient selenium, which is incorporated into 25 different selenium-containing proteins. Many selenoproteins function as antioxidants, supporting a role for selenium in protecting against oxidative stress.
Christopher Williams, MD, PhD, professor of Medicine, and his team have focused on selenoprotein P, which is unique among selenoproteins because it has both antioxidant and selenium transport function. It is produced and secreted primarily by the liver to transport selenium throughout the body.
In previous studies, Williams and his colleagues found that reducing overall selenoprotein P levels increased colitis-associated cancer in a mouse model. Now, they have probed the precise source of selenoprotein P using tissue-specific strategies to delete the protein from the liver, myeloid (immune system) cells or colonic epithelial cells. They found that deletion of selenoprotein P from colonic cells, but not from the liver or myeloid cells, increased colitis-associated cancer.
“We were surprised to discover that liver-produced selenoprotein P — the major source of plasma selenoprotein P — did not appear to be relevant to gut-specific tumorigenesis,” said Sarah Short, PhD, research instructor in Medicine and first author of the Gastroenterology report.
The findings have special clinical relevance, she said, because selenium levels are assessed in part by measuring selenoprotein P in the plasma, which reflects mostly liver production.
“Our studies suggest that using plasma selenoprotein P levels as a biomarker for disease, as is often done clinically, may not reflect the biology in the tissue microenvironment,” Short said.
Working with colleagues at Cincinnati Children’s Hospital, the researchers demonstrated that selenoprotein P levels are reduced in colon biopsy samples from patients with ulcerative colitis and that selenoprotein P levels were inversely correlated with disease severity.
“Selenoprotein P in colon tissue samples might be a useful biomarker to assess disease severity and monitor risk for colitis-associated cancer,” Williams said.
The researchers noted that increased tumor development is likely due to elevated oxidative stress and genomic instability. In ongoing studies, they are exploring how selenoprotein P exerts antitumorigenic effects.
“Knowing that selenoprotein P generated in the colon protects the epithelial cells from injury and progression to tumorigenesis is an important discovery. It extends our understanding of antioxidant systems in the colon and will help focus our future investigations,” Williams said.
Short, who recently received a Mentored Research Scientist Career Development Award (K01) from the National Institutes of Health, will explore the roles of other selenoproteins in inflammatory bowel disease.
Studies of selenium biology have a long history at Vanderbilt, beginning with seminal biochemistry and transport studies conducted by emeritus professor Raymond Burk, MD, who is also an author of the current study. Other Vanderbilt authors include Jennifer Pilat, Caitlyn Barrett, Vishruth Reddy, Jared Hendren, Benjamin Marsh, Cody Keating, Amy Motley, Kristina Hill, M. Kay Washington and Keith Wilson.
The research was supported by the National Institutes of Health (grants DK009204, AT004821, DK058404, CA167920, DK108492, DK103498, CA232272, DK117119, DK095745), Department of Veterans Affairs and Crohn’s and Colitis Foundation.