title: Loss of intestinal O-glycans promotes spontaneous duodenal tumors.
abstract: Mucin-type O-glycans, primarily core 1- and core 3-derived O-glycans, are the major mucus barrier components throughout the gastrointestinal tract. Previous reports identified the biological role of O-glycans in the stomach and colon. However, the biological function of O-glycans in the small intestine remains unknown. Using mice lacking intestinal core 1- and core 3-derived O-glycans [intestinal epithelial cell C1galt1(-/-);C3GnT(-/-) or double knockout (DKO)], we found that loss of O-glycans predisposes DKO mice to spontaneous duodenal tumorigenesis by ∼1 yr of age. Tumor incidence did not increase with age; however, tumors advanced in aggressiveness by 20 mo. O-glycan deficiency was associated with reduced luminal mucus in DKO mice before tumor development. Altered intestinal epithelial homeostasis with enhanced baseline crypt proliferation characterizes these phenotypes as assayed by Ki67 staining. In addition, fluorescence in situ hybridization analysis reveals a significantly lower bacterial burden in the duodenum compared with the large intestine. This phenotype is not reduced with antibiotic treatment, implying O-glycosylation defects, rather than bacterial-induced inflammation, which causes spontaneous duodenal tumorigenesis. Moreover, inflammatory responses in DKO duodenal mucosa are mild as assayed with histology, quantitative PCR for inflammation-associated cytokines, and immunostaining for immune cells. Importantly, inducible deletion of intestinal O-glycans in adult mice leads to analogous spontaneous duodenal tumors, although with higher incidence and heightened severity compared with mice with O-glycans constitutive deletion. In conclusion, these studies reveal O-glycans within the small intestine are critical determinants of duodenal cancer risk. Future studies will provide insights into the pathogenesis in the general population and those at risk for this rare but deadly cancer.
authors.affiliation: The Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma;
authors.forename: Kirk
authors.initials: K
authors.lastname: Bergstrom
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; and.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Fu
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; The Department of Gastroenterology and Hepatology, First Municipal People's Hospital of Guangzhou, Guangzhou Medical University, Guangdong, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Xie
authors.affiliation: The Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China;
authors.forename: Weichang
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma; Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; and lijun-Xia@omrf.org.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004379:Duodenal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004382:Duodenitis / Q000378:metabolism / Q000473:pathology; D004386:Duodenum / Q000378:metabolism* / Q000473:pathology; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics; D010641:Phenotype
chemical_list: C515597:C1galt1 protein, mouse; D005700:Galactosyltransferases; D017351:N-Acetylglucosaminyltransferases
keywords: duodenal tumor; mucin-type O-glycans; mucus layer