Sialyl Lewis x (sLex) is a
selectin ligand whose overexpression in epithelial
cancers mediates
metastasis formation. The molecular basis of sLex biosynthesis in
colon cancer tissues is still unclear. The prerequisite for therapeutic approaches aimed at sLex down-regulation in
cancer, is the identification of rate-limiting steps in its biosynthesis. We have studied the role of α1,3-fucosyltransferases (Fuc-Ts) potentially involved in sLex biosynthesis in specimens of normal and
cancer colon as well as in experimental systems. We found that: (i) in
colon cancer, but not in normal mucosa where the
antigen was poorly expressed, sLex correlated with a Fuc-T which, like Fuc-TVI, was active on 3'sialyllactosamine at a low concentration (Fuc-T(SLN)); (ii) competitive RT-PCR analysis revealed that the level of Fuc-T
mRNA expression in both normal and
cancer colon was Fuc-TVI>
Fuc-TIII>Fuc-TIV; Fuc-TV and Fuc-TVII expression was negligible; (iii) sLex was expressed only by the gastrointestinal cell lines displaying both Fuc-TVI
mRNA and Fuc-T(SLN) activity, but not by those expressing only
Fuc-TIII mRNA; (iv) transfection with Fuc-TVI
cDNA, but not with
Fuc-TIII cDNA, induced sLex expression in gastrointestinal cell lines; (v) Fuc-TVI knock-down with specific
siRNA induced down-regulation of Fuc-TVI
mRNA and Fuc-T(SLN) activity and a dramatic inhibition of sLex expression. These data indicate that in
colon cancer tissues Fuc-TVI is a key regulator of sLex biosynthesis which can be the target of RNA-interference-based gene knock-down approaches.