Loss of Disialyl Lewis, the Ligand for Lymphocyte Inhibitory Receptor Sialic Acid- Binding Immunoglobulin-Like Lectin-7 (Siglec-7) Associated with Increased Sialyl Lewis Expression on Human Colon Cancers

Expression of sialyl Lewis 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, which has an extra sialic acid attached at the C6-position of penultimate GlcNAc in sialyl Lewis, is expressed preferentially on nonmalignant colonic epithelial cells, and its expression decreases significantly on malignant transformation. Introduction of the gene for an 236 sialyltransferase responsible for disialyl Lewis synthesis to colon cancer cells resulted in a marked increase in disialyl Lewis expression and corresponding decrease in sialyl Lewis 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-dominant status to sialyl Lewis-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 236 sialyltransferase was markedly down-regulated in cancer cells compared with nonmalignant epithelial cells, which is in line with the decreased expression of disialyl Lewis and increased expression of sialyl Lewis in cancers. Treatment of cancer cells with butyrate or 5-azacytidine induced strongly disialyl Lewis expression, suggesting that histone deacetylation and/or DNA methylation may be involved in the silencing of the gene in cancers.