Hypersialylation of beta1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility.
Colon adenocarcinomas are known to express elevated levels of alpha2-6 sialylation and increased activity of ST6Gal-I, the Golgi glycosyltransferase that creates alpha2-6 linkages. Elevated ST6Gal-I positively correlates with metastasis and poor survival, and therefore ST6Gal-I-mediated hypersialylation likely plays a role in colorectal tumor invasion. Previously we found that oncogenic ras (present in roughly 50% of colon adenocarcinomas) up-regulates ST6Gal-I and, in turn, increases sialylation of beta1 integrin adhesion receptors in colon epithelial cells. However, we wanted to know if this pattern held true in vivo and, if so, how beta1 hypersialylation might contribute to colon tumor progression. In the present study, we find that beta1 integrins from colon adenocarcinomas consistently carry higher levels of alpha2-6 sialic acid. To explore the effects of increased alpha2-6 sialylation on beta1-integrin function, we stably expressed ST6Gal-I in a colon epithelial cell line lacking endogenous ST6Gal-I. ST6Gal-I expressors (with alpha2-6 sialylated beta1 integrins) exhibited up-regulated attachment to collagen I and laminin and increased haptotactic migration toward collagen I, relative to parental cells (with completely unsialylated beta1 integrins). Blockade of ST6Gal-I expression with short interfering RNA reversed collagen binding back to the level of ST6Gal-I nonexpressors, confirming that alpha2-6 sialylation regulates beta1 integrin function. Finally, we show that beta1 integrins from ST6Gal-I expressors have increased association with talin, a marker for integrin activation. Collectively, these findings suggest that beta1 hypersialylation may augment colon tumor progression by altering cell preference for certain extracellular matrix milieus, as well as by stimulating cell migration.
Seales
Eric C
EC
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Jurado
Gustavo A
GA
Brunson
Brian A
BA
Wakefield
John K
JK
Frost
Andra R
AR
Bellis
Susan L
SL
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D012799:Sialyltransferases / Q000096:biosynthesis / Q000378:metabolism; D016608:Talin / Q000378:metabolism; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
D024042:Collagen Type I; D019012:Integrin beta1; D007797:Laminin; D012794:Sialic Acids; D016608:Talin; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase