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

Abstract

The core 3 structure of the O-glycan, GlcNAc␤1-3GalNAc␣1-Ser͞ Thr, an important precursor in the biosynthesis of mucin-type glycoproteins, is synthesized by ␤1,3-N-acetylglucosaminyltransferase 6 (␤3Gn-T6; core 3 synthase). We generated an anti-␤3Gn-T6 mAb (G8-144 mAb) and performed immunohistochemical analyses. In normal stomach and colon, ␤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 ␤3Gn-T6 expression and the degree of dysplasia͞neoplasia. In vitro, the level of ␤3Gn-T6 transcript was increased according to the differentiation of Caco-2 cells. These results suggested that the expression of ␤3Gn-T6 is closely regulated during differentiation and dedifferentiation. ␤3Gn-T6 would be a useful marker for distinguishing between benign adenomas and premalignant lesions. HT1080 FP-10 cells stably transfected with the ␤3Gn-T6 gene showed a decrease in the core 1 structure, Gal␤1,3GalNAc␣1-Ser͞ 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.glycosyltransferase ͉ stomach ͉ familial adenomatous polyposis ͉ immunohistochemical analysis

C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells

“…By stable transfection of HCT116 cells, we found that C2GnT-M also decreased the core 1 structure, suggesting that this could be due to the processing of the core 1 structure (T antigen) to core 2 through C2GnT activity of C2GnT-M. Core 3 synthase was found to be significantly downregulated in colon cancer (Iwai et al, 2005). In addition, we could not detect I antigen expression on mock and C2GnT-M transfectants of HCT116.…”

β1,4-N-Acetylgalactosaminyltransferase III Enhances Malignant Phenotypes of Colon Cancer Cells

“…Recently, we found that C2GnT-M overexpression decreases colon cancer cell growth and tyrosine phosphorylation of paxillin, which is an important downstream signaling molecule of integrins (12). In addition, h3Gn-T6 was found to decrease core 1 structure and suppress metastatic potential of colon carcinoma cells through an unclear mechanism (13). These studies suggest that glycosyltransferases can regulate cancer cell behavior through alterations of integrin glycosylation or through other mechanisms which remain to be identified.…”

Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

“…Expression of core3 synthase in a human fibrosarcoma cell line also resulted in decreased lung tumor foci formation compared with mock-transfected cells (16). However, these studies did not address the mechanisms regarding how core3 synthase expression results in decreased tumor formation and decreased tumor metastasis.…”