title: Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.
abstract: Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.
authors.forename: Caitlyn W
authors.initials: CW
authors.lastname: Barrett
authors.forename: Vishruth K
authors.initials: VK
authors.lastname: Reddy
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Short
authors.forename: Amy K
authors.initials: AK
authors.lastname: Motley
authors.forename: Mary K
authors.initials: MK
authors.lastname: Lintel
authors.forename: Amber M
authors.initials: AM
authors.lastname: Bradley
authors.forename: Tanner
authors.initials: T
authors.lastname: Freeman
authors.forename: Jefferson
authors.initials: J
authors.lastname: Vallance
authors.forename: Wei
authors.initials: W
authors.lastname: Ning
authors.forename: Bobak
authors.initials: B
authors.lastname: Parang
authors.forename: Shenika V
authors.initials: SV
authors.lastname: Poindexter
authors.forename: Barbara
authors.initials: B
authors.lastname: Fingleton
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Mary K
authors.initials: MK
authors.lastname: Washington
authors.forename: Keith T
authors.initials: KT
authors.lastname: Wilson
authors.forename: Noah F
authors.initials: NF
authors.lastname: Shroyer
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Hill
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Burk
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Williams
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004249:DNA Damage; D042822:Genomic Instability; D057895:Haploinsufficiency; D008264:Macrophages / Q000145:classification / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress; D017434:Protein Structure, Tertiary; D012643:Selenium / Q000008:administration & dosage / Q000378:metabolism; D051149:Selenoprotein P / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D000975:Antioxidants; D051149:Selenoprotein P; D025521:Tumor Suppressor Proteins; D012643:Selenium