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. 2012 Jan 30;2(1):34-45.
doi: 10.3390/biom2010034.

Fucosylation is a promising target for cancer diagnosis and therapy

Eiji Miyoshi  1 , Kenta Moriwaki  2 , Naoko Terao  2 , Cheng-Cheng Tan  2 , Mika Terao  2 , Tsutomu Nakagawa  2 , Hitoshi Matsumoto  2 , Shinichiro Shinzaki  2 , Yoshihiro Kamada  2
Affiliations

Fucosylation is a promising target for cancer diagnosis and therapy

Eiji Miyoshi et al. Biomolecules. .

Abstract

Oligosaccharides, sequences of carbohydrates conjugated to proteins and lipids, are arguably the most abundant and structurally diverse class of molecules. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. Recent advances in glycomics have identified several types of glyco-biomarkers containing fucosylation that are linked to certain types of cancer. Fucosylated alpha-fetoprotein (AFP) is widely used in the diagnosis of hepatocellular carcinoma because it is more specific than alpha-fetoprotein. High levels of fucosylated haptoglobin have also been found in sera of patients with various carcinomas. We have recently established a simple lectin-antibody ELISA to measure fucosylated haptoglobin and to investigate its clinical use. Cellular fucosylation is dependent upon fucosyltransferase activity and the level of its donor substrate, guanosine diphosphate (GDP)-fucose. GDP-mannose-4,6-dehydratase (GMDS) is a key enzyme involved in the synthesis of GDP-fucose. Mutations of GMDS found in colon cancer cells induced a malignant phenotype, leading to rapid growth in athymic mice resistant to natural killer cells. This review describes the role of fucosylated haptoglobin as a cancer biomarker, and discusses the possible biological role of fucosylation in cancer development.

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Figures

Figure 1
Figure 1
Fucosylated haptoglobin is a novel cancer biomarker for differential diagnosis and predicted prognosis. (A) Lectin blot using aleuria aurantia lectin (AAL) detected a protein of approximately 40 kDa from sera of patients with pancreatic cancer. Coomassie Brilliant Blue staining showed no changes in levels of this protein. This figure is cited from reference [22] with slight modification; (B) Establishment of lectin-antibody ELISA kit to measure Fuc-Hpt. Schematic system is shown; (C) Representative data of the Fuc-Hpt ELISA kit. Seventy-two cases of patients with pancreatic cancer and 22 healthy volunteers were assayed with 25 times dilution of sera. This data is cited from reference [28] with slight modification; (D) Combination assay of Fuc-Hpt and carcinoembryonic antigen is a marker for poor prognosis in patients with colorectal cancer after operation. This data is cited from reference [23] with slight modification.
Figure 2
Figure 2
Deficiency of GDP-mannose-4,6-dehydratase (GMDS) leads to escape from natural killer (NK) cell-mediated tumor surveillance through modulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling. (A) After transfection of wild-type GMDS gene into HCT116 cells, Western blot analysis of GMDS and AAL was performed. The binding to AAL was restored in transfected cells (WT-GMDS). Each number represents an independent clone; (B) Tumor growth of GMDS-rescued cells on the backs of athymic nude mice was significantly suppressed compared to mock cells. Rejected tumors at one month after transplantation were photographed; (C) The higher susceptibility of the GMDS-rescued cells to recombinant human TRAIL was confirmed by Western blotting of cleavedpoly (adenosine diphosphate-ribose) polymerase (PARP), which is a signal of apoptosis; (D) Complex II formation after TRAIL treatment was inhibited in HCT 116 cells which lacked cellular fucosylation. Immunoprecipitaion of FADD followed by Western blotting of caspase 8, c-Flip, and cleaved PARP were performed on HCT 116 clones treated with TRAIL. Detailed procedures are described in reference [29]. All data were derived from references [11,29].
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