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

¹ Department of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya; ² Science and Technology Agency, Kawaguchi; ³ Central Clinical Laboratory, Kyoto University Hospital, Kyoto; ⁴ Second Department of Biochemistry, Nagoya University School of Medicine, Nagoya; ⁵ Department of Applied Bio-Organic Chemistry, Gifu University, Gifu; ⁶ Glyco-Chain Functions Laboratory, Supra-Biomolecular System Group, Frontier Research System, RIKEN Institute, Saitama; and ⁷ Central Laboratories for Key Technology, Kirin Brewery Company, Yokohama, Japan

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 26 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 26 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.

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