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Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma.
Wang, Yiwei; Huang, Dan; Chen, Kai-Yuan; Cui, Min; Wang, Weihuan; Huang, Xiaoran; Awadellah, Amad; Li, Qing; Friedman, Ann; Xin, William W; Di Martino, Luca; Cominelli, Fabio; Miron, Alex; Chan, Ricky; Fox, James G; Xu, Yan; Shen, Xiling; Kalady, Mathew F; Markowitz, Sanford; Maillard, Ivan; Lowe, John B; Xin, Wei; Zhou, Lan.
Affiliation
  • Wang Y; Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • Huang D; Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • Chen KY; Department of Biomedical Engineering, Cornell University, Ithaca, New York.
  • Cui M; Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • Wang W; Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • Huang X; Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • Awadellah A; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
  • Li Q; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
  • Friedman A; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
  • Xin WW; School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Di Martino L; Department of Internal Medicine, University Hospitals Case Medical Center, Cleveland, Ohio.
  • Cominelli F; Department of Internal Medicine, University Hospitals Case Medical Center, Cleveland, Ohio.
  • Miron A; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
  • Chan R; Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.
  • Fox JG; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts.
  • Xu Y; Department of Chemistry, Cleveland State University, Cleveland, Ohio.
  • Shen X; Department of Biomedical Engineering, Cornell University, Ithaca, New York.
  • Kalady MF; Department of Colorectal Surgery, Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio.
  • Markowitz S; Department of Medicine, Case Western Reserve University, Cleveland, Ohio.
  • Maillard I; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan.
  • Lowe JB; Department of Pathology, Genentech, Inc, San Francisco, California.
  • Xin W; Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio.
  • Zhou L; Department of Pathology, Case Western Reserve University, Cleveland, Ohio; Department of Pathology, University Hospitals Case Medical Center, Cleveland, Ohio. Electronic address: lan.zhou@case.edu.
Gastroenterology ; 152(1): 193-205.e10, 2017 01.
Article in En | MEDLINE | ID: mdl-27639802
ABSTRACT
BACKGROUND &

AIMS:

De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis.

METHODS:

FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided).

RESULTS:

Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues.

CONCLUSIONS:

In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.
Subject(s)
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carbohydrate Epimerases / Adenocarcinoma / Colitis / Colon / Colonic Neoplasms / Intestinal Mucosa / Ketone Oxidoreductases Type of study: Prognostic_studies Limits: Aged80 Language: En Journal: Gastroenterology Year: 2017 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carbohydrate Epimerases / Adenocarcinoma / Colitis / Colon / Colonic Neoplasms / Intestinal Mucosa / Ketone Oxidoreductases Type of study: Prognostic_studies Limits: Aged80 Language: En Journal: Gastroenterology Year: 2017 Document type: Article
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