Expression of human alpha(1,3)fucosyltransferase antisense sequences inhibits selectin-mediated adhesion and liver metastasis of colon carcinoma cells.
The initial steps of leukocyte and tumor cell adhesion involve selectin receptor/ligand interactions. The selectin ligand components sialyl Lewis x and sialyl Lewis a are oncodevelopmental antigens involved in progression of adenocarcinoma. Interrupting biosynthesis of these surface glycans by inhibition of alpha(1,3)fucosyltransferase (FUT) gene expression is an attractive goal for functional and therapeutic studies. We report here the inhibition of E-selectin-mediated adenocarcinoma cell adhesion by stable transfection of antisense sequences directed at the human Lewis alpha(1,3/1,4)fucosyltransferase gene, FUT3. The metastatic parental cell line, HT-29LMM, expressed high levels of sialyl Lewis x, sialyl Lewis a, alpha(1,3/1,4)fucosyltransferase activity, and FUT3 transcript, but antisense transfectant cell lines did not. When injected into the spleens of nude mice, the stable antisense clones were unable to colonize the liver. These results provide target validation for inhibition of carcinoma metastasis with antisense FUT sequences and confirm the primacy of alpha(1,3)fucosyltransferases in the synthesis of selectin ligands.
Weston
B W
BW
The Lineberger Comprehensive Cancer Center, Department of Pediatrics, University of North Carolina, Chapel Hill 27599-7220, USA. bwwmd@med.unc.edu
Hiller
K M
KM
Mayben
J P
JP
Manousos
G A
GA
Bendt
K M
KM
Liu
R
R
Cusack
J C
JC
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control / Q000556:secondary / Q000628:therapy*; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D018395:CA-19-9 Antigen; D002448:Cell Adhesion; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D016373:DNA, Antisense / Q000235:genetics*; D018450:Disease Progression; D019040:E-Selectin / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D005647:Fucosyltransferases / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005732:Gangliosides / Q000096:biosynthesis*; D005822:Genetic Vectors / Q000235:genetics* / Q000627:therapeutic use; D006031:Glycosylation; D006801:Humans; D007267:Injections; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D009368:Neoplasm Transplantation; D009844:Oligosaccharides / Q000096:biosynthesis*; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D000080506:Sialyl Lewis X Antigen; D013154:Spleen; D014162:Transfection; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D018395:CA-19-9 Antigen; D016373:DNA, Antisense; D019040:E-Selectin; D005732:Gangliosides; D009363:Neoplasm Proteins; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; C064564:sialyl Le(a) ganglioside; D005647:Fucosyltransferases; C019818:3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase