alpha 2-6-Linked sialic acids on N-glycans modulate carcinoma differentiation in vivo

Cancer Res. 2008 Jan 15;68(2):388-94. doi: 10.1158/0008-5472.CAN-07-1340.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma / enzymology
  • Carcinoma / genetics
  • Carcinoma / pathology*
  • Cell Differentiation
  • Disease Progression
  • Female
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Expression Regulation, Enzymologic
  • Integrin beta1 / metabolism
  • Mammary Neoplasms, Experimental / enzymology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Polysaccharides / chemistry*
  • Polysaccharides / metabolism
  • Polysaccharides / physiology
  • Sialic Acids / chemistry
  • Sialic Acids / metabolism
  • Sialic Acids / physiology*
  • Sialyltransferases / genetics
  • Sialyltransferases / metabolism
  • Sialyltransferases / physiology*
  • Signal Transduction / genetics
  • Tumor Cells, Cultured

Substances

  • Integrin beta1
  • Polysaccharides
  • Sialic Acids
  • Sialyltransferases
  • beta-D-galactoside alpha 2-6-sialyltransferase
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse