title: alpha 2-6-Linked sialic acids on N-glycans modulate carcinoma differentiation in vivo.
abstract: Sialic acids on vertebrate cell surfaces mediate many biological roles. Altered expression of certain sialic acid types or their linkages can have prognostic significance in human cancer. A classic but unexplained example is enhanced alpha2-6-sialylation on N-glycans resulting from overexpression of the Golgi enzyme beta-galactoside:alpha2-6-sialyltransferase (ST6Gal-I). Previous data supporting a role for the resulting Sia alpha 2-3Gal beta 1-4GlcNAc (Sia6LacNAc) structure in tumor biology were based on in vitro studies in transfected carcinoma cells, in which increased Sia6LacNAc on beta1-integrins enhanced their binding to ligands, and stimulated cell motility. Here, we examine for the first time the in vivo role of the ST6Gal-I enzyme in the growth and differentiation of spontaneous mammary cancers in mice transgenic for a mouse mammary tumor virus promoter-driven polyomavirus middle T antigen, a tumor in which beta1-integrin function is important for tumorigenesis and in maintaining the proliferative state of tumor cells. Tumors induced in St6gal1-null animals were more differentiated compared with those in the wild-type background, both by histologic analysis and by protein expression profiles. Furthermore, we show the St6gal1-null tumors have selectively altered expression of genes associated with focal adhesion signaling and have decreased phosphorylation of focal adhesion kinase, a downstream target of beta1-integrins. This first in vivo evidence for a role of ST6Gal-I in tumor progression was confirmed using a novel approach, which conditionally restored St6gal1 in cell lines derived from the null tumors. These findings indicate a role for ST6Gal-I as a mediator of tumor progression, with its expression causing a less differentiated phenotype, via enhanced beta1-integrin function.
authors.affiliation: Glycobiology Research and Training Center, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0687, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hedlund
authors.forename: Elisa
authors.initials: E
authors.lastname: Ng
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Nissi M
authors.initials: NM
authors.lastname: Varki
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D018450:Disease Progression; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D019012:Integrin beta1 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D011134:Polysaccharides / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D012794:Sialic Acids / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D019012:Integrin beta1; D011134:Polysaccharides; D012794:Sialic Acids; D012799:Sialyltransferases; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase