Mutation of GDP-Mannose-4,6-Dehydratase in Colorectal Cancer Metastasis

Nakayama, Keizo; Moriwaki, Kazuo; Imai, Taku; Shinzaki, Shinichiro; Kamada, Y.; Murata, Kohei; Miyoshi, Eiji

doi:10.1371/journal.pone.0070298

Cited by 32 publications

(19 citation statements)

References 18 publications

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“…Interestingly, mutations in VCAN have been implicated in several ophthalmologic disorders (29). Of interest, known POAG genes also fit in the pathways identified in this study, for example GAS7 and SIX6 play a role during development (27,30), TGFBR3 has been implicated in extracellular matrix regulation (31) and in cancer as well as GMDS (32). Common variants in CDKN2B and its antisense CDKN2B-AS1 have been robustly found associated with POAG.…”

Section: à5supporting

confidence: 54%

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

et al. 2017

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Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

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Section: à5supporting

confidence: 54%

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

et al. 2017

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“…These data were not further developed and need to be evaluated on the light of recent papers dealing with the derangement of fucosylation occurring in cancer. A general loss of the fucosylation potential has been reported in fact in up to 13% of colorectal cancers due to mutations of an enzyme involved in the biosynthesis of GDP-Fuc [86,87], the mandatory donor of fucose in all fucosyltransferase-catalyzed reactions. Such mutation and the consequent loss of fucosylation was very recently reported to enhance inflammation and tumors in the mouse [88].…”

Section: Regulation Of Slea and Slexmentioning

confidence: 99%

Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers

Trinchera

Aronica

Dall’Olio

2017

Biology

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The tetrasaccharide structures Siaα2,3Galβ1,3(Fucα1,4)GlcNAc and Siaα2,3Galβ1,4(Fucα1,3)GlcNAc constitute the epitopes of the carbohydrate antigens sialyl-Lewis a (sLea) and sialyl-Lewis x (sLex), respectively, and are the minimal requirement for selectin binding to their counter-receptors. Interaction of sLex expressed on the cell surface of leucocytes with E-selectin on endothelial cells allows their arrest and promotes their extravasation. Similarly, the rolling of cancer cells ectopically expressing the selectin ligands on endothelial cells is potentially a crucial step favoring the metastatic process. In this review, we focus on the biosynthetic steps giving rise to selectin ligand expression in cell lines and native tissues of gastrointestinal origin, trying to understand whether and how they are deregulated in cancer. We also discuss the use of such molecules in the diagnosis of gastrointestinal cancers, particularly in light of recent data questioning the ability of colon cancers to express sLea and the possible use of circulating sLex in the early detection of pancreatic cancer. Finally, we reviewed the data dealing with the mechanisms that link selectin ligand expression in gastrointestinal cells to cancer malignancy. This promising research field seems to require additional data on native patient tissues to reach more definitive conclusions.

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“…For example, increase in fucosylated alpha-fetoprotein is seen in sera of patients with hepatocellular carcinoma 21 . By comparison, loss of fucosylation due to mutation of GMDS is reported in colon cancer cell lines and up to 13% of colorectal cancer (CRC) tissues 22, 23 . A search of the Cancer Genome Atlas (TCGA) reveals that homozygous deletions of GMDS are found in 2% of a published CRC database and in 5.5% of a provisional database 24 (www.cbioportal.org).…”

Section: Introductionmentioning

confidence: 99%

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

et al. 2017

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Background & Aims De novo synthesis of GDP-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or TSTA3). GMDS deletions and mutations are found in 6%–13% of colorectal cancers; these mostly affect ascending and transverse colon. We investigated whether lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. Methods FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx–/– mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by ELISAs to measure cytokine levels; T cells were also collected and analyzed. Fecal samples were analyzed by 16s rRNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx–/– or control mice (Ly5.2) into irradiated 8-week old Fx–/– or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). Results Fx–/– mice developed colitis and serrated-like lesions. The intestinal pathology of Fx–/– mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx–/– mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function and altered epithelial proliferation marked by Ki67. Fx–/– mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MLH1 had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. Conclusions In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and downregulation of Hes1. HES1 loss correlates with development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.

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Mutation of GDP-Mannose-4,6-Dehydratase in Colorectal Cancer Metastasis

Cited by 32 publications

References 18 publications

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma

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