title: Post-translational glycoprotein modifications regulate colon cancer stem cells and colon adenoma progression in Apc(min/+) mice through altered Wnt receptor signaling.
abstract: Deletion of GnT-V (MGAT5), which synthesizes N-glycans with β(1,6)-branched glycans, reduced the compartment of cancer stem cells (CSC) in the her-2 mouse model of breast cancer, leading to delay of tumor onset. Because GnT-V levels are also commonly up-regulated in colon cancer, we investigated their regulation of colon CSC and adenoma development. Anchorage-independent cell growth and tumor formation induced by injection of colon tumor cells into NOD/SCID mice were positively associated with GnT-V levels, indicating regulation of proliferation and tumorigenicity. Using Apc(min/+) mice with different GnT-V backgrounds, knock-out of GnT-V had no significant effect on the number of adenoma/mouse, but adenoma size was significantly reduced and accompanied increased survival of Apc(min/+) mice with GnT-V deletion (p < 0.01), suggesting an inhibition in the progression of colon adenoma caused by deletion of GnT-V. Decreased expression levels of GnT-V down-regulated the population of colon (intestine) CSC, affecting their ability for self-renewal and tumorigenicity in NOD/SCID mice. Furthermore, altered nuclear translocation of β-catenin and expression of Wnt target genes were positively associated with expression levels of GnT-V, indicating the regulation of canonical Wnt/β-catenin signaling. By overexpressing the Wnt receptor, FZD-7, in colon cancer cells, we found that FZD-7 receptors expressed N-linked β(1,6) branching, indicating that FZD-7 can be modified by GnT-V. The aberrant Wnt signaling observed after modulating GnT-V levels is likely to result from altered N-linked β(1,6) branching on FZD-7, thereby affecting Wnt signaling, the compartment of CSC, and tumor progression.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center and hbguo@uga.edu.
authors.forename: Huabei
authors.initials: H
authors.lastname: Guo
authors.affiliation: Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602.
authors.forename: Tamas
authors.initials: T
authors.lastname: Nagy
authors.affiliation: From the Departments of Biochemistry and Molecular Biology, Complex Carbohydrate Research Center and hawkeye@uga.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Pierce
mesh_terms: D021581:Active Transport, Cell Nucleus; D000236:Adenoma / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006026:Glycoside Hydrolases / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase; D006026:Glycoside Hydrolases
keywords: Apcmin/+ Mice; Cancer Stem Cells; Colon Cancer; Gene Knockout; GnT-V; N-Linked Glycosylation; Wnt Signaling