Core 3 synthase is down-regulated in colon carcinoma and profoundly suppresses the metastatic potential of carcinoma cells

The core 3 structure of the O-glycan, GlcNAc beta 1-3GalNAc alpha 1-Ser/ Thr, an important precursor in the biosynthesis of mucin-type glycoproteins, is synthesized by beta 1,3-N-acetylglucosaminyltransferase 6 (beta Gn-T6; core 3 synthase). We generated an anti-beta 3Gn-T6 mAb (G8-144 mAb) and performed immunohistochemical analyses. In normal stomach and colon, beta 3Gn-T6 was strongly expressed in the Golgi region of epithelia. In contrast, its expression was markedly down-regulated in gastric and colorectal carcinomas. Tissue specimens from a familial adenomatous polyposis patient showed a clear correlation between the down-regulation of beta 3Gn-T6 expression and the degree of dysplasia/neoplasia. In vitro, the level of beta 3Gn-T6 transcript was increased according to the differentiation of Caco-2 cells. These results suggested that the expression of beta 3Gn-T6 is closely regulated during differentiation and dedifferentiation. beta 3Gn-T6 would be a useful marker for distinguishing between benign adenomas and premalignant lesions. HT1080 FP-10 cells stably transfected with the beta 3Gn-T6 gene showed a decrease in the core 1 structure, Gal beta 1,3GalNAc alpha 1-Ser/ Thr, probably due to competition between the core 1 synthase and care 3 synthase. The migration activity of the transfectants was markedly lower than that of mock transfectants in vitro, and lung metastasis after i.v. injection of the transfectants into nude mice was significantly suppressed. These findings indicated that the core structures of O-glycans are profoundly involved in the metastatic capacity of cancer cells.