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Hypersialylation of ß₁ Integrins, Observed in Colon Adenocarcinoma, May Contribute to Cancer Progression by Up-regulating Cell Motility

Departments of ¹ Pathology and ² Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama and ³ Tranzyme, Inc., Research Triangle Park, North Carolina

Requests for reprints: Susan L. Bellis, Department of Physiology and Biophysics, Room 982A MCLM, 1918 University Boulevard, Birmingham, AL 35294. Phone: 205-934-3441; Fax: 205-975-9028; E-mail: bellis{at}physiology.uab.edu.

Colon adenocarcinomas are known to express elevated levels of 2-6 sialylation and increased activity of ST6Gal-I, the Golgi glycosyltransferase that creates 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 ß₁ integrin adhesion receptors in colon epithelial cells. However, we wanted to know if this pattern held true in vivo and, if so, how ß₁ hypersialylation might contribute to colon tumor progression. In the present study, we find that ß₁ integrins from colon adenocarcinomas consistently carry higher levels of 2-6 sialic acid. To explore the effects of increased 2-6 sialylation on ß₁-integrin function, we stably expressed ST6Gal-I in a colon epithelial cell line lacking endogenous ST6Gal-I. ST6Gal-I expressors (with 2-6 sialylated ß₁ integrins) exhibited up-regulated attachment to collagen I and laminin and increased haptotactic migration toward collagen I, relative to parental cells (with completely unsialylated ß₁ integrins). Blockade of ST6Gal-I expression with short interfering RNA reversed collagen binding back to the level of ST6Gal-I nonexpressors, confirming that 2-6 sialylation regulates ß₁ integrin function. Finally, we show that ß₁ integrins from ST6Gal-I expressors have increased association with talin, a marker for integrin activation. Collectively, these findings suggest that ß₁ hypersialylation may augment colon tumor progression by altering cell preference for certain extracellular matrix milieus, as well as by stimulating cell migration.

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