Molecular bases of sialyl Lewis x overexpression in colon cancer

Sialyl Lewis x (sLex) is a well known selectin ligand involved in metastasis. The molecular bases of its overexpression in colon cancer are still unclear. Here we show that FucT-VI is the main fucosyltransferase responsible for sLex biosynthesis in colonic tissues and a major regulator of sLex expression in colon cancer because: 1) in colon cancer specimens and cell lines sLex expression correlates with the activity of a fucosyltransferase able to fucosylate 3’ sialyllactosamine (3’SLN) at a low (0.5 mM) acceptor concentration. 2) In cells transiently transfected with FucT genes only FucT-VI displays this property. 3) In normal and cancer colon, FucT-VI transcript shows the highest level of expression (about 200 fg/pg actin, vs. 30 for FucT-III, 10 for FucT-IV, <1 for FucT-V while FucT-VII was undetectable). However, neither the FucT-VI transcript nor the activity on 3’SLN are increased in cancer tissues. In normal mucosa, sLex (which can be detected upon de-acetylation), does not correlate with FucT-VI activity. This is due to the concomitant high expression of beta4GalNAcT-II, the synthase of the Sda antigen [Sia alpha2,3(GalNAc beta1,4)Galbeta1,4GlcNAc], which competes with fucosyltransferases for 3’-sialylated type 2 chains and is downregulated in colon cancer. In fact, in normal mucosa sLex expression correlates with the ratio between the activities of FucT-VI and that of beta4GalNAcT-II. These findings explain why sLex antigen overexpression in cancer is not necessarily related to FucT-VI overexpression, and point to the balance between FucT-VI and beta4GalNAcT-II as a pivotal regulator of sLex in colon.