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Tumor Biology |
The Chicago Institute of Neurosurgery and Neuroresearch, Chicago, Illinois 60614 [H. Y., J. S., S. G., T. S., J. H., C. S., J. L., E. M., L. C., J. R. M.], and Department of Biochemistry, Osaka University Medical School, Osaka 565, Japan [A. N., Y. I., N. T.]
The metastatic potential of tumor cells has been shown to be correlated with the expression of tri- and tetra-antennary ß1,6-N-acetylglucosamine (ß1,6-GlcNAc)-bearing N-glycans, which are recognized by Phaseolus vulgaris leukoagglutinating lectin (L-PHA). The expression of ß1,6-GlcNAc-bearing N-glycans also has been used as a marker of tumor progression in human breast and colon cancers. In this report, the role of N-glycan branching in regulating glioma migration and invasion was examined. The expression of ß1,6-GlcNAc-bearing N-glycans was found in human glioma specimens, whereas astrocytes from normal adult brain were negative. The expression of N-acetylglucosaminyltransferase V (GnT-V) mRNA, which is responsible for the biosynthesis of ß1,6-GlcNAc-bearing N-glycans, was high in glioma cell lines with robust ets-1 expression. To study the molecular mechanism of GnT-V expression in human glioma cells, an inducible ets-1 gene was stably transfected into SNB-19 cells using a tetracycline repressor system. GnT-V mRNA expression was increased by the induction of c-ets-1, suggesting that the Ets-1 transcription factor directly regulates the transcription of GnT-V. Stable transfection of GnT-V into human glioma U-373 MG cells resulted in changes in cell morphology and focal adhesions and a marked increase in glioma invasivity in vitro. L-PHA has little effect on cell migration. On the contrary, Phaseolus vulgaris erythroagglutinating lectin (E-PHA), which recognizes bisecting ß1,4-GlcNAc-bearing N-glycans, strongly inhibits cell migration (haptotaxis) on a fibronectin substrate in U-373 MG transfectants and other glioma cell lines tested. These results suggest that the increased ß1,6-GlcNAc-bearing N-glycan expression found in malignant gliomas is modulated by GnT-V through the Ets-1 transcription factor, and that the branching of complex type N-glycans plays a major role in glioma invasivity.
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