Expression and enzyme activity of α(1,6)fucosyltransferase in human colorectal cancer

Muinelo-Romay, L.; Vázquez-Martín, Cristina; Villar-Portela, Susana; Cuevas, Elisa; Gil‐Martín, Emilio; Fernández-Briera, Almudena

doi:10.1002/ijc.23521

Cited by 77 publications

(92 citation statements)

References 26 publications

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“…Many studies have described the up-regulation of α(1,2), α(1,3/4) and α(1,6)fucosyltransferases in different types of tumours and, subsequently, the importance of their fucosylated products in tumour development and progression (15)(16)(17). therefore, the accumulation of lewis antigens, terminal fucosylated oligosaccharides present in glycolipids and glycoproteins, has been associated with the processes of adhesion and endothelial extravasation of tumour cells, both being important steps that mediate hematogenous metastasis.…”

Section: Discussionmentioning

confidence: 99%

α(1,2)fucosylation in human colorectal carcinoma

Muinelo-Romay

Gil‐Martín²,

Fernández-Briera³

2010

Oncology Letters

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Abstract. lewis b and lewis y (le) antigens are known to be elevated in colorectal tumours. Alterations in the catalytic behaviour of gDP-l-fucose:β-D-galactoside α(1,2) fucosyltransferase [α(1,2)Ft, ec: 2.4.1.69], the key enzyme in their synthesis, have been suggested as being responsible for these changes. In particular, an aberrant tumour-specific α(1,2)Ft activity that converts le a and le x to le b and le y determinants, respectively, has been reported in colorectal cancer tissues. to clarify the catalytic function of this enzyme during colorectal tumorigenesis, we analyzed α(1,2)Ft activity levels in healthy and tumour colon specimens using different acceptor substrates and determined the kinetic properties of the enzyme. to complete the study, the aberrant le a /le x α(1,2) fucosylation was determined in healthy and tumour colorectal tissues. A correlation analysis between the activity levels and various standard clinicopathological features, such as tumour stage, was also carried out to elucidate the role of these activities in tumour progression. The results obtained confirm the enhanced α(1,2)fucosylation in colorectal neoplastic tissues and the importance of the aberrant le a /le x α(1,2)Ft activity in this increase. However, taking into account the high levels of le a /le x fucosylation observed in healthy control tissues, we must rule out the idea of a colorectal tumour-specific α(1,2) FT. On the other hand, no significant association was observed between α(1,2)Ft activity levels and the clinicopathological characteristics. overall, our results suggest that α(1,2)Ft activity plays a critical role in the accumulation of le b and le y antigens in human colorectal carcinoma. IntroductionAlterations in glycosylation patterns are one of the characteristics associated with differentiation and malignant transformation (1). the oligosaccharide portions of cellular glycoconjugates, glycolipids and glycoproteins, convey specific immunodeterminants, such as the blood group and related antigens (2). these antigens are known to play an important role in cell recognition, interaction, adhesion and motility. Accordingly, changes in these antigens during carcinogenesis may be crucial in tumour progression and may be involved in extravasation and metastatic phenomena (3).ABo and related determinants are the result of the sequential addition of monosaccharide units to one of the five disaccharide precursors described. type 1 [galβ (1,3)glcnac β1-r] and 2 [gal β(1,4)glcnac β1-r] precursors produce H 1 and H 2 structures, respectively, after the addition of a fucose in α(1,2) linkage to the terminal β-galactosyl residue. H 1 and H 2 determinants can subsequently be converted into le b and le y difucosylated antigens by fucosylation in α(1,4) or α(1,3) linkage, respectively. their positional isomers, the le a and le x antigens, show a similar structure, but the antigens are not fucosylated in α(1,2) (4). Specific alterations of Lewis antigens have been reported in multiple carcinomas and have been correlated with the pr...

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Section: Discussionmentioning

confidence: 99%

α(1,2)fucosylation in human colorectal carcinoma

Muinelo-Romay

Gil‐Martín²,

Fernández-Briera³

2010

Oncology Letters

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“…So far, 13 FUTs are known to be encoded by the human genome, including FUT1 to 11, protein O-fucosyltransferase 1 (POFUT1), and POFUT2. Through these FUTs, fucoses could be attached to N-, O-, and lipid-linked glycans through an α1,2-(by FUT1 and 2), α1,3-(by FUT3 to 7 and FUT9 to 11), α1,4-(by FUT3 and 5), or α1,6-(by FUT8) linkage, or directly link to the serine/threonine residues of EGF-like or thrombospondin repeats (by POFUT1 and 2, respectively) (1,2).…”

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confidence: 99%

“…The up-regulation of FUT8 mRNA, protein, and activity has been observed in several malignant tumors including liver, ovarian, thyroid, and colorectal cancers, and linked to the severity of cancers (13)(14)(15)(16). For example, in papillary thyroid carcinoma, higher expression of FUT8 is linked to bigger tumor sizes and more metastases in lymph nodes; in colorectal carcinoma, the expression of FUT8 is associated with poor prognosis.…”

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confidence: 99%

Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer

Chen

Jan

Juan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

226

199

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The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial-mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.TGF-beta | E-cadherin | fucose F ucosylation, the transfer of fucose from GDP-fucose to glycoconjugates such as glycoproteins and glycolipids, is catalyzed by a family of enzymes called fucosyltransferases (FUTs). So far, 13 FUTs are known to be encoded by the human genome, including FUT1 to 11, protein O-fucosyltransferase 1 (POFUT1), and POFUT2. Through these FUTs, fucoses could be attached to N-, O-, and lipid-linked glycans through an α1,2-(by FUT1 and 2), α1,3-(by FUT3 to 7 and FUT9 to 11), α1,4-(by FUT3 and 5), or α1,6-(by FUT8) linkage, or directly link to the serine/threonine residues of EGF-like or thrombospondin repeats (by POFUT1 and 2, respectively) (1, 2). In mammals, fucosylated glycans have pivotal roles in many aspects of biological processes such as lymphocyte homing, immune responses, fertilization, and development (3). Moreover, aberrant fucosylation, which results from the deficiency or overexpression of FUTs, is associated with a variety of human diseases, including cystic fibrosis, leukocyte adhesion deficiency type II, and cancers (3, 4).Unlike other FUTs, which are functionally redundant, FUT8 is the only enzyme responsible for the α1,6-linked (core) fucosylation by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions. For example, deletion of the core fucose from the Fc region of IgG1 greatly improves its binding affinity to Fcγ receptor IIIa, which in turn enhances antibody-dependent cell-mediated cytotoxicity for over 50 folds (5, 6). Co...

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“…Many studies show that alterations in asparagine-linked oligosaccharides of tumor cells are associated with carcinogenesis, invasion, and metastasis [10,11,12]. Among 13 fucosyltransferases known to be encoded by the human genome, fucosyltransferase 8 (FUT8) is the only enzyme to catalyze the transfer of a fucosyl moiety from guanosine diphosphate (GDP)-fucose to the innermost GlcNAc residue of hybrid and complex asparagine-linked oligosaccharides in glycoprotein via α1,6 linkage to form core fucosylation, which is frequently observed in malignant transformation [13,14,15,16,17,18]. Increased FUT8 activity is certainly an important factor in the regulation of fucosylation, although other factors may be involved in its regulation, such as the synthesis of GDP- L -fucose (GDP- L -Fuc), the substrate for FUT8.…”

Section: Introductionmentioning

confidence: 99%

Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers

Honma¹,

Kinoshita²,

Miyoshi

et al. 2015

Oncology

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Objecitive: Fucosyltransferase 8 (FUT8), the only enzyme responsible for the core α1,6-fucosylation of asparagine-linked oligosaccharides of glycoproteins, is a vital enzyme in cancer development and progression. We examined FUT8 expression in non-small cell lung cancers (NSCLCs) to analyze its clinical significance. We also examined the expression of guanosine diphosphate-mannose-4,6-dehydratase (GMD), which is imperative for the synthesis of fucosylated oligosaccharides. Methods: Using immunohistochemistry, we evaluated the expression of FUT8 and GMD in relation to patient survival and prognosis in potentially curatively resected NSCLCs. Results: High expression of FUT8 was found in 67 of 129 NSCLCs (51.9%) and was significantly found in non-squamous cell carcinomas (p = 0.008). High expression of FUT8 was associated with poor survival (p = 0.03) and was also a significant and independent unfavorable prognostic factor in patients with potentially curatively resected NSCLCs (p = 0.047). High expression of GMD was significantly associated with high FUT8 expression (p = 0.04). Conclusions: High expression of FUT8 is associated with an unfavorable clinical outcome in patients with potentially curatively resected NSCLCs, suggesting that FUT8 can be a prognostic factor. The analysis of FUT8 expression and its core fucosylated products may provide new insights for the therapeutic targets of NSCLCs.

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Expression and enzyme activity of α(1,6)fucosyltransferase in human colorectal cancer

Cited by 77 publications

References 26 publications

α(1,2)fucosylation in human colorectal carcinoma

α(1,2)fucosylation in human colorectal carcinoma

Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer

Expression of Fucosyltransferase 8 Is Associated with an Unfavorable Clinical Outcome in Non-Small Cell Lung Cancers

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