Intestinal Sulfation Is Essential to Protect Against Colitis and Colonic Carcinogenesis.
Journal Article (Journal Article)
BACKGROUND & AIMS: Sulfation is a conjugation reaction essential for numerous biochemical and cellular functions in mammals. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. The goal of this study was to determine whether and how PAPSS2 plays a role in colitis and colonic carcinogenesis. METHODS: Tissue arrays of human colon cancer specimens, gene expression data, and clinical features of cancer patients were analyzed. Intestinal-specific Papss2 knockout mice (Papss2ΔIE) were created and subjected to dextran sodium sulfate-induced colitis and colonic carcinogenesis induced by a combined treatment of azoxymethane and dextran sodium sulfate or azoxymethane alone. RESULTS: The expression of PAPSS2 is decreased in the colon cancers of mice and humans. The lower expression of PAPSS2 in colon cancer patients is correlated with worse survival. Papss2ΔIE mice showed heightened sensitivity to colitis and colon cancer by damaging the intestinal mucosal barrier, increasing intestinal permeability and bacteria infiltration, and worsening the intestinal tumor microenvironment. Mechanistically, the Papss2ΔIE mice exhibited reduced intestinal sulfomucin content. Metabolomic analyses revealed the accumulation of bile acids, including the Farnesoid X receptor antagonist bile acid tauro-β-muricholic acid, and deficiency in the formation of bile acid sulfates in the colon of Papss2ΔIE mice. CONCLUSIONS: We have uncovered an important role of PAPSS2-mediated sulfation in colitis and colonic carcinogenesis. Intestinal sulfation may represent a potential diagnostic marker and PAPSS2 may serve as a potential therapeutic target for inflammatory bowel disease and colon cancer.
Full Text
Duke Authors
Cited Authors
- Xu, P; Xi, Y; Zhu, J; Zhang, M; Luka, Z; Stolz, DB; Cai, X; Xie, Y; Xu, M; Ren, S; Huang, Z; Yang, D; York, JD; Ma, X; Xie, W
Published Date
- July 2021
Published In
Volume / Issue
- 161 / 1
Start / End Page
- 271 - 286.e11
PubMed ID
- 33819483
Pubmed Central ID
- PMC8238844
Electronic International Standard Serial Number (EISSN)
- 1528-0012
Digital Object Identifier (DOI)
- 10.1053/j.gastro.2021.03.048
Language
- eng
Conference Location
- United States