Expression of
sialyl Lewis(a) is known to be increased in
cancers of the digestive organs. The determinant serves as a
ligand for
E-selectin and mediates hematogenous
metastasis of
cancers. In contrast, disialyl Lewis(a), which has an extra
sialic acid attached at the C6-position of penultimate GlcNAc in
sialyl Lewis(a), is expressed preferentially on nonmalignant colonic epithelial cells, and its expression decreases significantly on malignant transformation. Introduction of the gene for an alpha2-->6 sialyl-
transferase responsible for disialyl Lewis(a) synthesis to
colon cancer cells resulted in a marked increase in disialyl Lewis(a) expression and corresponding decrease in
sialyl Lewis(a) expression. This was accompanied by the complete loss of
E-selectin binding activity of the cells. In contrast, the transfected cells acquired significant binding activity to
sialic acid-binding
immunoglobulin-like lectin-7 (
Siglec-7)/p75/adhesion inhibitory receptor molecule-1, an inhibitory receptor expressed on lymphoid cells. These results indicate that the transition of
carbohydrate determinants from disialyl Lewis(a)-dominant status to
sialyl Lewis(a)-dominant status on malignant transformation has a dual functional consequence: the loss of normal cell-cell recognition between mucosal epithelial cells and lymphoid cells on one hand and the gain of
E-selectin binding activity on the other. The transcription of a gene encoding the alpha2-->6
sialyltransferase was markedly down-regulated in
cancer cells compared with nonmalignant epithelial cells, which is in line with the decreased expression of disialyl Lewis(a) and increased expression of
sialyl Lewis(a) in
cancers. Treatment of
cancer cells with
butyrate or
5-azacytidine induced strongly disialyl Lewis(a) expression, suggesting that
histone deacetylation and/or DNA methylation may be involved in the silencing of the gene in
cancers.