3'-Azidothymidine may potently inhibit the biosynthesis of polylactosamine chains on highly glycosylated-CD147 and reduce matrix metalloproteinase-2 expression in SGC-7901 and U251 cells.

Alterations to N­linked glycans are closely associated with cancer progression. Of particular importance in tumor growth and invasion, is the synthesis of complex N­linked oligosaccharides containing poly­N­acetyllactosamine (polylactosamine) chains, which have previously been reported to inhibit 3'­azidothymidine (AZT). Cluster of differentiation 147 (CD147) is a glycoprotein that carries ß1,6­branched polylactosamine sugars on its N­glycans. The present study aimed to explore the mechanism by which AZT may affect matrix metalloproteinase­2 (MMP2) expression and the cell cycle via regulation of the N­glycans on CD147 in SGC­7901 and U251 cell lines. Subsequent to treatment with various concentrations of AZT, the N­glycans of highly glycosylated (HG)­CD147 were observed to decrease in the two cell lines, and the expression of MMP2 was also significantly decreased. In addition, cell cycle analysis demonstrated that the percentage of the cells in the G1 phase increased in a dose­dependent manner with AZT treatment, indicating that AZT may inhibit cell proliferation in SGC­7901 cells. It was suggested that AZT may reduce the biosynthesis of polylactosamine chains on CD147 and reduce MMP2 expression to inhibit cell proliferation in SGC­7901 and U251 cells. Thus, AZT is suggested to be an antineoplastic drug, which may be effective therapeutically for certain types of cancer through acting on the N­glycans of HG­CD147.

High expression of ß3GnT8 is associated with the metastatic potential of human glioma.

Changes in glycosylation due to specific alterations of glycosyltransferase activity have been shown in various tumor cells, including human glioma cells. ß1,3-N­acetylglucosaminyltransferase-8 (ß3GnT8) catalyzes the formation of polylactosamine on ß1-6 branched N-glycans. Upregulated expression of ß3GnT8 was described in some tumors, but its precise role in regulating glioma invasion and metastasis remains unclear. In this study, we report on an investigation of the expression of ß3GnT8 in human glioma by immunohistochemical analysis. Out of 42 glioma tissues, 37 (88.1%) showed positive ß3GnT8 expression, which was significantly higher than that in normal brain tissues (P<0.001). Additionally, the level of ß3GnT8 increased with increased pathological grade of gliomas. Silencing of ß3GnT8 in U251 glioma cells attenuated the formation of polylactosamine, and decreased cell proliferation, migration and metastatic ability in vitro and in vivo. By contrast, the overexpression of ß3GnT8 in U251 cells exhibited enhanced metastatic potential. A positive correlation between ß3GnT8 and matrix metalloproteinase-2 (MMP-2) expression in U251 cells was also observed. The results demonstrated a critical role of ß3GnT8 in the metastatic potential of glioma cells, indicating that manipulating ß3GnT8 expression may have therapeutic potential for the treatment of malignant glioma.

ß3GnT8 plays an important role in CD147 signal transduction as an upstream modulator of MMP production in tumor cells.

Aberrant carbohydration by related glycosyl-transferases plays an important role in the progression of cancer. This study focused on the ablity of ß-1,3-N-acetyl-glucosaminyltransferase-8 (ß3GnT8) to regulate MMP-2 expression through regulation of the CD147 signal transduction pathway in cancer cells. ß3GnT8 catalyzes and then extends a polylactosamine chain specifically on ß1-6-branched tetraantennary N-glycans. CD147 is a major carrier of ß1-6-branched polylactosamine sugars on tumor cells, and the high glycoform of CD147 (HG-CD147) induces matrix metalloproteinase (MMP) production. In the present study, we analyzed ß3GnT8 mRNA expression in 6 cancer cell lines (MCF-7, M231, LN229, U87, SGC-7901 and U251). We found that ß3GnT8 expression in the LN229, SGC-7901 and U251 cell lines was higher than that in the other cell lines. Therefore, we established ß3GnT8-knockdown cell lines derived from the LN229 and SGC-7901 cell lines to examine the level of polylactosamine and CD147 N-glycosylation. In addition, tunicamycin is widely used as an inhibitor of N-linked glycosylation. Hence, various concentrations of tunicamycin were used to treat the cells in order to study its influence on CD147 N-glycosylation and MMP-2 expression. In conclusion, we found that ß3GnT8 regulated the level of N-glycans on CD147 and that N-glycosylation of CD147 has an important effect on MMP-2 expression. Our findings suggest that ß3GnT8 affects the signal transduction pathway of MMP-2 by altering the N-glycan structure of CD147.