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.
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.
Miyazaki
Keiko
K
Department of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Ohmori
Katsuyuki
K
Izawa
Mineko
M
Koike
Tetsufumi
T
Kumamoto
Kensuke
K
Furukawa
Koichi
K
Ando
Takayuki
T
Kiso
Makoto
M
Yamaji
Toshiyuki
T
Hashimoto
Yasuhiro
Y
Suzuki
Akemi
A
Yoshida
Aruto
A
Takeuchi
Makoto
M
Kannagi
Reiji
R
D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D018395:CA-19-9 Antigen; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D037102:Lectins / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012799:Sialyltransferases / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D015214:Antigens, Differentiation, Myelomonocytic; D015295:Antigens, Tumor-Associated, Carbohydrate; D018395:CA-19-9 Antigen; D018076:DNA, Complementary; D037102:Lectins; D012333:RNA, Messenger; C402206:SIGLEC7 protein, human; C476448:disialyl Lewis a antigen; C476449:GalNAc sialyltransferase VI; D012799:Sialyltransferases