A high expression of GDP-fucose transporter in hepatocellular carcinoma is a key factor for increases in fucosylation.
Changes in the levels of fucosylation regulate the biological phenotype of cancer cells and a specific fucosylation, such as fucosylated alpha-fetoprotein (AFP-L3) has been clinically used as a tumor marker for hepatocellular carcinoma (HCC). However, detailed molecular mechanisms that explain the increased fucosylation in HCC remain unknown despite 10 years of study by these researchers. Fucosylation is regulated by complicated mechanisms that involve several factors: fucosyltransferases, GDP-fucose transporter (GDP-Fuc Tr), and synthetic enzymes of GDP-fucose, such as GDP-mannose 4, 6-dehydratase (GMD), GDP-4-keto-6-deoxy-mannose-3, 5-epimerase-4-reductase (FX), and GDP-fucose pyrophosphorylase. In this study, the expression of fucosylation-related genes in HCC tissues was studied and it was found that GDP-Fuc Tr is a key factor for increases in fucosylation. A real-time reverse transcription polymerase chain reaction (RT-PCR) analysis showed significant increases in GDP-Fuc Tr and FX expression in HCC, and levels of the GMD protein were upregulated by posttranslational modification in HCC tissues. In vitro cell experiments showed that the level of GDP-Fuc Tr was the most significantly correlated with the level of cellular fucosylation and the overexpression of GDP-Fuc Tr dramatically increased fucosylation in Hep3B cells. The importance of GDP-Fuc Tr in the increase of fucosylation was also confirmed with immunohistochemical analyses. These findings suggest that the upregulation of GDP-Fuc Tr plays a pivotal role in increased fucosylation in HCC and represents an attractive target for new treatments and diagnosis for HCC.
Moriwaki
Kenta
K
Department of Molecular Biochemistry & Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Noda
Katsuhisa
K
Nakagawa
Takatoshi
T
Asahi
Michio
M
Yoshihara
Harumasa
H
Taniguchi
Naoyuki
N
Hayashi
Norio
N
Miyoshi
Eiji
E
D000368:Aged; D001692:Biological Transport; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005643:Fucose / Q000737:chemistry* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006153:Guanosine Diphosphate / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009004:Monosaccharide Transport Proteins / Q000378:metabolism / Q000502:physiology*; D009844:Oligosaccharides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism
D009004:Monosaccharide Transport Proteins; D009844:Oligosaccharides; D012333:RNA, Messenger; C426650:SLC35C1 protein, human; D006153:Guanosine Diphosphate; D005643:Fucose