Tumor cell migration and invasion are regulated by expression of variant integrin glycoforms.
The ST6Gal-I glycosyltransferase, which adds alpha2-6-linked sialic acids to glycoproteins, is overexpressed in colon adenocarcinoma, and enzyme activity is correlated with tumor cell invasiveness. Previously we reported that forced expression of oncogenic ras in HD3 colonocytes causes upregulation of ST6Gal-I, leading to increased alpha2-6 sialylation of beta1 integrins. To determine whether ras-induced sialylation is involved in promoting the tumor cell phenotype, we used shRNA to downregulate ST6Gal-I in ras-expressors, and then monitored integrin-dependent responses. Here we show that forced ST6Gal-I downregulation, leading to diminished alpha2-6 sialylation of integrins, inhibits cell adhesion to collagen I, a beta1 ligand. Correspondingly, collagen binding is reduced by enzymatic removal of cell surface sialic acids from ras-expressors with high ST6Gal-I levels (i.e., no shRNA). Cells with forced ST6Gal-I downregulation also exhibit decreased migration on collagen I and diminished invasion through Matrigel. Importantly, GD25 cells, which lack beta1 integrins (and ST6Gal-I), do not demonstrate differential invasiveness when forced to express ST6Gal-I, suggesting that the effects of variant sialylation are mediated specifically by beta1 integrins. The observation that cell migration and invasion can be blocked in oncogenic ras-expressing cells by forcing ST6Gal-I downregulation implicates differential sialylation as an important ras effector, and also suggests that ST6Gal-I is a promising therapeutic target.
Shaikh
Faheem M
FM
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Seales
Eric C
EC
Clem
William C
WC
Hennessy
Kristin M
KM
Zhuo
Ya
Y
Bellis
Susan L
SL
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009439:Neuraminidase / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D024042:Collagen Type I; D016023:Integrins; D020033:Protein Isoforms; D012794:Sialic Acids; D012799:Sialyltransferases; D009439:Neuraminidase; D018631:ras Proteins; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase