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

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National Academy of Sciences

RESUMO

The core 3 structure of the O-glycan, GlcNAcβ1-3GalNAcα1-Ser/Thr, an important precursor in the biosynthesis of mucin-type glycoproteins, is synthesized by β1,3-N-acetylglucosaminyltransferase 6 (β3Gn-T6; core 3 synthase). We generated an anti-β3Gn-T6 mAb (G8-144 mAb) and performed immunohistochemical analyses. In normal stomach and colon, β3Gn-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 β3Gn-T6 expression and the degree of dysplasia/neoplasia. In vitro, the level of β3Gn-T6 transcript was increased according to the differentiation of Caco-2 cells. These results suggested that the expression of β3Gn-T6 is closely regulated during differentiation and dedifferentiation. β3Gn-T6 would be a useful marker for distinguishing between benign adenomas and premalignant lesions. HT1080 FP-10 cells stably transfected with the β3Gn-T6 gene showed a decrease in the core 1 structure, Galβ1,3GalNAcα1-Ser/Thr, probably due to competition between the core 1 synthase and core 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.

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