Hypersialylation of β1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility

Colon adenocareinomas are known to express elevated levels of alpha 2-6 sialylation and increased activity of ST6Gal-I, the Golgi glycosyltransferase that creates alpha 2-6 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 beta(1) integrin adhesion receptors in colon epithelial cells. However, we wanted to know if this pattern held true in vivo and, if so, how beta(1) hypersialylation might contribute to colon tumor progression. In the present study, we find that 0] integrins from colon adenocarcinomas consistently carry higher levels of alpha 2-6 sialic acid. To explore the effects of increased alpha 2-6 sialylation on beta(1)-integrin function, we stably expressed ST6Gal-I in a colon epithelial cell line lacking endogenous ST6Gal-I. ST6GaI-I expressors (with alpha 2-6 sialylated beta(1) integrins) exhibited up-regulated attachment to collagen I and laminin and increased haptotactic migration toward collagen I relative to parental cells (with completely unsialylated beta(1) integrins). Blockade of ST6Gal-I expression with short interfering RNA reversed collagen binding back to the level of ST6Gal-I nonexpressors, confirming that alpha 2-6 sialylation regulates beta(1) integrin function. Finally, we show that beta(1) integrins from ST6Gal-I expressors have increased association with talin, a marker for integrin activation. Collectively, these findings suggest that beta(1) hypersialylation may augment colon tumor progression by altering cell preference for certain extracellular matrix milieus, as well as by stimulating cell migration.