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Relationship between Elevated FX Expression and Increased Production of GDP-L-Fucose, a Common Donor Substrate for Fucosylation in Human Hepatocellular Carcinoma and Hepatoma Cell Lines¹

Department of Biochemistry [K. N., J. G., C-X. G., S. N., T. K., K. H., N. T.], Department of Molecular Biochemistry and Clinical Investigations [K. N., E. M., C-X. G.], Department of Molecular Therapeutics, Division of Molecular Therapy Science [K. N., N. H.], Department of Internal Medicine and Therapeutics [K. N., M. H.], and Department of General Medicine [A. K.], Osaka University, Graduate School of Medicine, Osaka, Japan; Departments of Gastroenterology [K. S., H. Y.], Surgery [K. Y.], and Pathology [K. K.], Osaka Rosai Hospital, Osaka, 565-0871, Japan; Department of Experimental Medicine, University of Genova and Center of Excellence for Biomedical Research, 16132 Genova, Italy [M. T.], and Department of Molecular Genetics, Kochi Medical School, Kochi 783-8505, Japan [K. H.]

The levels of fucosylated glycoproteins in various cancers and inflammatory processes have been a subject of intense study. The level of fucosyltransferases and intracellular GDP-L-fucose, a sugar nucleotide and a common donor substrate for all fucosyltransferases, may regulate the level of fucosylated glycoproteins. This study reports on the determination of GDP-L-fucose levels in human hepatocellular carcinoma (HCC) and surrounding tissues, using a recently established high-throughput assay system. Levels of GDP-L-fucose in HCC tissues were significantly increased compared with adjacent nontumor tissues or normal livers. The mean ± SD for GDP-L-fucose level was 3.6 ± 0.2 µmol/mg in control liver, 4.6 ± 0.9 µmol/mg in adjacent noninvolved liver tissues (chronic hepatitis, 4.4 ± 0.7 µmol/mg; liver cirrhosis, 4.8 ± 0.9 µmol/mg), and 7.1 ± 2.5 µmol/mg in HCC tissues. The level of GDP-L-fucose in HCC decreased in proportion with tumor size (r = -0.675, P = 0.0002). When expression of the series of genes responsible for GDP-L-fucose synthesis was investigated, the gene expression of FX was found to be increased in 70% (7 of 10) of the HCC tissues examined compared with that in their surrounding tissues. The levels of GDP-L-fucose were positively correlated with the expression of FX mRNA (r = 0.599, P = 0.0074). The levels of FX gene expression in some human hepatoma and hepatocyte cell lines were determined. FX mRNA production was strongly increased in HepG2 and Chang liver, moderately increased in Hep3B and HLF, and, in HLE, was similar to that of a normal human liver tissue. To investigate the effect of GDP-L-fucose on core fucosylation, FX cDNA was transfected into Hep3B cells, which express a relatively low level of GDP-L-fucose:N-acetyl-ß-D-glucosaminide 1-6 fucosyltransferase (1-6 FucT) and FX mRNA. Transfection of this gene caused an increase in GDP-L-fucose levels as well as the extent of fucosylation on glycoproteins, including -fetoprotein, as judged by reactivity to lectins. Collectively, the results herein suggest that the high level of fucosylation in HCC is dependent on a high expression of FX followed by increases in GDP-L-fucose, as well as an enhancement in 1-6 FucT expression. Thus, an elevation in GDP-L-fucose levels and the up-regulation of FX expression represent potential markers for HCC.

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