Gene expression of α1-6 fucosyltransferase in human hepatoma tissues: A possible implication for increased fucosylation of α-fetoprotein

Noda, Katsuhisa; Miyoshi, Eiji; Uozumi, Naonori; Yanagidani, Shusaku; Ikeda, Yoshitaka; Gao, Can; Suzuki, Kazutoshi; Yoshihara, Hiroyuki; Yoshikawa, Masumi; Kawano, Kiyoshi; Hayashi, Norio; Hori, Masatsugu; Taniguchi, Naoyuki

doi:10.1002/hep.510280408

Cited by 128 publications

(88 citation statements)

References 30 publications

(36 reference statements)

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“…We also isolated a genomic clone for the human α1,6FucT gene (FUT8) and used this to map the gene on human chromosome 14q24.3 by fluorescence in situ hybridization (Yamaguchi et al, 1999). Northern blot analyses have shown that a good correlation exists between the increased α1,6FucT activities in hepatocellular carcinomas and the elevated levels of the FUT8 mRNA Noda et al, 1997Noda et al, , 1998. This supports the view that the FUT8 is certainly responsible for the increased fucosylation which is associated with hepatocellular carcinoma.…”

Section: Introductionsupporting

confidence: 55%

Genomic structure and promoter analysis of the human 1,6-fucosyltransferase gene (FUT8)

Yamaguchi¹,

Ikeda²,

Takahashi³

et al. 2000

Glycobiology

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GDP-L-Fuc:N-acetyl-β-D-glucosaminide α1,6-fucosyltransferase (α1,6FucT) catalyzes the transfer of a fucosyl moiety from GDP-fucose to the asparagine-linked GlcNAc residue of complex N-glycans via α1,6-linkage. We have cloned the genomic DNA which encodes the human α1,6FucT gene (FUT8) and analyzed its structure. It was found that the gene consists of at least nine exons spanning more than a 50 kbp genomic region, and the coding sequence is divided into eight exons. The translation initiation codon was located at exon 2, and thus exon 1 encodes only 5′-untranslated sequences. Transcription initiation site of FUT8 was determined by 5′-rapid amplification of the cDNA end and a primer-extension analysis using the total RNA isolated from SK-OV-3 cells, which have a high level of α1,6FucT activity. We then characterized the FUT8 promoter region by a reporter gene assay. The luciferase reporter assay indicated that the 5′-flanking region of exon 1, which covered about 1 kbp, conferred the promoter activity in SK-OV-3 cells. This region contains potential binding sites for some transcription factors, such as bHLH, cMyb, GATA-1, as well as a TATAbox, but not a CCAAT motif. 5′-Untranslated sequences found in ESTs and the cDNA for the FUT8 suggest the presence of an additional exon(s) at the upstream of the first exon identified in this study, and therefore, the transcription of the gene would be regulated by multiple promoters.

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Section: Introductionsupporting

confidence: 55%

Genomic structure and promoter analysis of the human 1,6-fucosyltransferase gene (FUT8)

Yamaguchi¹,

Ikeda²,

Takahashi³

et al. 2000

Glycobiology

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“…Previously, the increased FUT8 mRNA level in the liver was also shown in patients with chronic hepatitis and liver cirrhosis (34). In the liver of patients with type 2 DM, various changes are caused by insufficient insulin action (37).…”

Section: Discussionmentioning

confidence: 89%

“…␣1,6-Fucosyltransferase (FUT8) is the only reported enzyme that catalyzes ␣1,6-fucosylation in mammals (29). Elevated expression of FUT8 was observed in human ovarian serous adenocarcinoma (40), hepatoma, and liver cirrhosis (34) and was linked to tumor size and lymph node metastasis in thyroid papillary carcinoma (20). Recently, the function of ␣1,6-fucosylation was analyzed using FUT8-deficient mice (45).…”

mentioning

confidence: 99%

Analysis ofN-glycan in serum glycoproteins fromdb/dbmice and humans with type 2 diabetes

Itoh¹,

Sakaue²,

Nakagawa³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Glycosylation has an important role in regulating properties of proteins and is associated with many diseases. To examine the alteration of serum N-glycans in type 2 diabetes, we used the db/db mouse model. Serum N-glycans were fluorescence labeled and applied to HPLC. There were reproducible differences in N-glycan profiles between the db/db mouse model and the db/+ control. The structures of the oligosaccharides, which had changed in their amounts, were analyzed by a two-dimensional mapping method, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, and exoglycosidase digestion. Those analyses revealed an increase in the N-glycans possessing α1,6-fucose in the serum of db/db mice. The level of α1,6-fucosyltransferase mRNA was increased in the liver of the db/db mice. The ratio of a biantennary N-glycan with α1,6-fucose to that without α1,6-fucose in the liver tissue of the db/db mouse was increased relative to the db/+ control. Next, we analyzed the serum N-glycan profile in human subjects with type 2 diabetes and found an increased amount of a biantennary N-glycan that had an α1,6-fucose with a bisecting N-acetylglucosamine. In conclusion, the increase in α1,6-fucosylation is a striking change in the serum N-glycans of the db/db mice, whereas the change in the fucosylation in humans with type 2 diabetes was small, albeit statistically significant. It is likely that the change is caused, at least partially, by the increase in the α1,6-fucosyltransferase mRNA level in the liver. The increased α1,6-fucosylation may affect protein properties associated with the pathophysiology of type 2 diabetes.

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“…An N-glycan profiling study identified novel N-glycan structures in serum as prognostic markers of hepatocellular carcinoma (11). In addition, a-1,6-fucosyltransferase can generate fucosylated a-fetoprotein (AFP), which provided a more accurate diagnosis of hepatocellular carcinoma from chronic liver diseases (12,13). However, changes in O-linked glycosylation have been overlooked in the past.…”

Section: Introductionmentioning

confidence: 99%

C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells via Modulating MET Glycosylation and Dimerization

Liu

Huang

et al. 2013

Cancer Research

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Altered glycosylation is a hallmark of cancer. The core 1 b1,3-galactosyltransferase (C1GALT1) controls the formation of mucin-type O-glycans, far overlooked and underestimated in cancer. Here, we report that C1GALT1 mRNA and protein are frequently overexpressed in hepatocellular carcinoma tumors compared with nontumor liver tissues, where it correlates with advanced tumor stage, metastasis, and poor survival. Enforced expression of C1GALT1 was sufficient to enhance cell proliferation, whereas RNA interferencemediated silencing of C1GALT1 was sufficient to suppress cell proliferation in vitro and in vivo. Notably, C1GALT1 attenuation also suppressed hepatocyte growth factor (HGF)-mediated phosphorylation of the MET kinase in hepatocellular carcinoma cells, whereas enforced expression of C1GALT1 enhanced MET phosphorylation. MET blockade with PHA665752 inhibited C1GALT1-enhanced cell viability. In support of these results, we found that the expression level of phospho-MET and C1GALT1 were associated in primary hepatocellular carcinoma tissues. Mechanistic investigations showed that MET was decorated with O-glycans, as revealed by binding to Vicia villosa agglutinin and peanut agglutinin. Moreover, C1GALT1 modified the O-glycosylation of MET, enhancing its HGF-induced dimerization and activation. Together, our results indicate that C1GALT1 overexpression in hepatocellular carcinoma activates HGF signaling via modulation of MET O-glycosylation and dimerization, providing new insights into how O-glycosylation drives hepatocellular carcinoma pathogenesis. Cancer Res; 73(17); 5580-90. Ó2013 AACR.

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Gene expression of α1-6 fucosyltransferase in human hepatoma tissues: A possible implication for increased fucosylation of α-fetoprotein

Cited by 128 publications

References 30 publications

Genomic structure and promoter analysis of the human 1,6-fucosyltransferase gene (FUT8)

Genomic structure and promoter analysis of the human 1,6-fucosyltransferase gene (FUT8)

Analysis ofN-glycan in serum glycoproteins fromdb/dbmice and humans with type 2 diabetes

C1GALT1 Enhances Proliferation of Hepatocellular Carcinoma Cells via Modulating MET Glycosylation and Dimerization

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