Biosynthesis and expression of the Sda and sialyl Lewis x antigens in normal and cancer colon.
The carbohydrate determinants Sd(a) and sialyl Lewis x (sLex) both result from substitution of an alpha2,3-sialylated type 2 chain: the first with an N-acetylgalactosamine (GalNAc) beta1,4-linked to Gal and the second by an alpha1,3-linked fucose on N-acetylglucosamine. The Sd(a) antigen is synthesized by Sd(a) beta1,4-N-acetylgalactosaminyltransferase II (beta4GalNAcT-II), which is downregulated in colon cancer, whereas sLex is a cancer-associated antigen. In view of the possible competition between beta4GalNAcT-II and the fucosyltransferases (FucTs) synthesizing the sLex antigen, we investigated whether beta4GalNAcT-II acts as a negative regulator of sLex expression in colon cancer. beta4GalNAcT-II cDNA, when expressed in LS174T colon cancer cells, induces the expression of the Sd(a) antigen, a dramatic inhibition of sLex expression on cell membranes, and the replacement of sLex with the Sd(a) antigen on 290 kDa glycoproteins. Unexpectedly, in colorectal cancer specimens, beta4GalNAcT-II and sLex show a direct relation. The reasons appear to be (i) Sd(a) and sLex antigens are expressed by different glycoproteins of 340 and 290 kDa, respectively; (ii) the activity of alpha1,3-FucTs on 3'-sialyllactosamine parallels that of beta4GalNAcT-II; and (iii) both beta4GalNAcT-II and FucT activities parallel sLex expression. Quantitative reverse transcription-polymerase chain reaction analysis reveals that the transcripts of beta4GalNAcT-II and those of FucT-III and FucT-VII are positively correlated. These data indicate that in colon cancer tissues, the sLex antigen is regulated mainly by the total FucT activity on 3'-sialyllactosamine acceptors and that beta4GalNAcT-II can inhibit sLex expression in an experimental model, although not in colon cancer tissues.
Malagolini
Nadia
N
Dipartimento di Patologia Sperimentale, Via S. Giacomo 14, 40126 Bologna, Italy.
Santini
Donatella
D
Chiricolo
Mariella
M
Dall'Olio
Fabio
F
D018938:Caco-2 Cells; D002236:Carbohydrate Conformation; D002241:Carbohydrates / Q000737:chemistry; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D005647:Fucosyltransferases / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016256:Lewis X Antigen / Q000096:biosynthesis / Q000737:chemistry*; D008954:Models, Biological; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism
D002241:Carbohydrates; D018076:DNA, Complementary; D016256:Lewis X Antigen; D005647:Fucosyltransferases; D017350:N-Acetylgalactosaminyltransferases