FUT1 and FUT2 encode alpha 1, 2-fucosyltransferases which catalyze the addition of alpha 1, 2-linked fucose to glycans. Glycan products of FUT1 and FUT2, such as Globo H and Lewis Y, are highly expressed on malignant tissues, including breast cancer. Herein, we investigated the roles of FUT1 and FUT2 in breast cancer. Silencing of FUT1 or FUT2 by shRNAs inhibited cell proliferation in vitro and tumorigenicity in mice. This was associated with diminished properties of cancer stem cell (CSC), including mammosphere formation and CSC marker both in vitro and in xenografts. Silencing of FUT2, but not FUT1, significantly changed the cuboidal morphology to dense clusters of small and round cells with reduced adhesion to polystyrene and extracellular matrix, including laminin, fibronectin and collagen. Silencing of FUT1 or FUT2 suppressed cell migration in wound healing assay, whereas FUT1 and FUT2 overexpression increased cell migration and invasion in vitro and metastasis of breast cancer in vivo. A decrease in mesenchymal like markers such as fibronectin, vimentin, and twist, along with increased epithelial like marker, E-cadherin, was observed upon FUT1/2 knockdown, while the opposite was noted by overexpression of FUT1 or FUT2. As expected, FUT1 or FUT2 knockdown reduced Globo H, whereas FUT1 or FUT2 overexpression showed contrary effects. Exogenous addition of Globo H-ceramide reversed the suppression of cell migration by FUT1 knockdown but not the inhibition of cell adhesion by FUT2 silencing, suggesting that at least part of the effects of FUT1/2 knockdown were mediated by Globo H. Our results imply that FUT1 and FUT2 play important roles in regulating growth, adhesion, migration and CSC properties of breast cancer, and may serve as therapeutic targets for breast cancer.

/pdf/fucosyltransferase-1-and-2-play-pivotal-roles-in-breast-5fa14v8xc9.pdf

Fucosyltransferase 1 and 2 play pivotal roles in breast cancer cells

Background One of the pathognomonic features of asthma is epithelial hyperproduction of mucus, which is composed of a series of glycoproteins; however, it remains unclear how glycosylation is induced in lung epithelial cells from asthmatic patients and how glycan residues play a role in the pathogenesis of asthma. Objective The objective of this study was to explore comprehensive epithelial glycosylation status induced by allergic inflammation and reveal its possible role in the pathogenesis of asthma. Methods We evaluated the glycosylation status of lung epithelium using a lectin microarray. We next searched for molecular mechanisms underlying epithelial glycosylation. We also examined whether epithelial glycosylation is involved in induction of allergic inflammation. Results On allergen inhalation, lung epithelial cells were heavily α(1,2)fucosylated by fucosyltransferase 2 (Fut2), which was induced by the IL-13–signal transducer and activator of transcription 6 pathway. Importantly, Fut2-deficient (Fut2−/−) mice, which lacked lung epithelial fucosylation, showed significantly attenuated eosinophilic inflammation and airway hyperresponsiveness in house dust mite (HDM)–induced asthma models. Proteome analyses and immunostaining of the HDM-challenged lung identified that complement C3 was accumulated in fucosylated areas. Indeed, Fut2−/− mice showed significantly reduced levels of C3a and impaired accumulation of C3a receptor–expressing monocyte-derived dendritic cells in the lung on HDM challenge. Conclusion Fut2 induces epithelial fucosylation and exacerbates airway inflammation in asthmatic patients in part through C3a production and monocyte-derived dendritic cell accumulation in the lung.

Fucosyltransferase 2 induces lung epithelial fucosylation and exacerbates house dust mite–induced airway inflammation

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.29029

Knockout of the primary sclerosing cholangitis-risk gene Fut2 causes liver disease in mice.

Necrotizing enterocolitis (NEC) is a life-threatening disease that predominantly affects very low birth weight preterm infants. Development of NEC in preterm infants is accompanied by high mortality. Surgical treatment of NEC can be complicated by short bowel syndrome, intestinal failure, parenteral nutrition-associated liver disease, and neurodevelopmental delay. Issues surrounding pathogenesis, prevention, and treatment of NEC remain unclear. This review summarizes data on prenatal risk factors for NEC, the role of pre-eclampsia, and intrauterine growth retardation in the pathogenesis of NEC. The role of hypoxia in NEC is discussed. Recent data on the role of the intestinal microbiome in the development of NEC, and features of the metabolome that can serve as potential biomarkers, are presented. The Pseudomonadota phylum is known to be associated with NEC in preterm neonates, and the role of other bacteria and their metabolites in NEC pathogenesis is also discussed. The most promising approaches for preventing and treating NEC are summarized.

/pdf/necrotizing-enterocolitis-the-role-of-hypoxia-gut-microbiome-1ra9n5uw.pdf

Necrotizing Enterocolitis: The Role of Hypoxia, Gut Microbiome, and Microbial Metabolites

Objectives Angiogenesis contributes to the pathogenesis of rheumatoid arthritis. Fucosyltransferases (Futs) are involved in angiogenesis and tumour growth. Here, we examined the role of Fut1 in angiogenesis and K/BxN serum transfer arthritis. Methods We examined Fut1 expression in human dermal microvascular endothelial cells (HMVECs) by quantitative PCR. We performed a number of angiogenesis assays to determine the role of Fut1 using HMVECs, Fut1 null ( Fut1 −/− ), and wild type (wt) endothelial cells (ECs) and mice. K/BxN serum transfer arthritis was performed to determine the contribution of Fut1-mediated angiogenesis in Fut1 −/− and wt mice. A static adhesion assay was implemented with RAW264.7 (mouse macrophage cell line) and mouse ECs. Quantitative PCR, immunofluorescence and flow cytometry were performed with Fut1 −/− and wt ECs for adhesion molecule expression. Results Tumour necrosis factor-α induced Fut1 mRNA and protein expression in HMVECs. HMVECs transfected with Fut1 antisense oligodeoxynucleotide and Fut1 −/− ECs formed significantly fewer tubes on Matrigel. Fut1 −/− mice had reduced angiogenesis in Matrigel plug and sponge granuloma angiogenesis assays compared with wt mice. Fut1 −/− mice were resistant to K/BxN serum transfer arthritis and had decreased angiogenesis and leucocyte ingress into inflamed joints. Adhesion of RAW264.7 cells to wt mouse ECs was significantly reduced when Fut1 was lacking. Fut1 −/− ECs had decreased intercellular adhesion molecule-1 (ICAM-1) expression at mRNA and protein levels compared with wt ECs. ICAM-1 was also decreased in Fut1 −/− arthritic ankle cryosections compared with wt ankles. Conclusions Fut1 plays an important role in regulating angiogenesis and ICAM-1 expression in inflammatory arthritis.

https://ard.bmj.com/content/annrheumdis/74/7/1459.full.pdf

A key role for Fut1-regulated angiogenesis and ICAM-1 expression in K/BxN arthritis

Objective

To better define the activity of soluble CXCL16 in the recruitment of polymorphonuclear neutrophils (PMNs) in vivo, utilizing a novel animal model of gout involving engraftment of SCID mice with normal human synovial tissue (ST) injected intragraft with gouty human synovial fluid (SF).



Methods

For in vitro studies, a modified Boyden chemotaxis system was used to identify CXCL16 as an active recruitment factor for PMNs in gouty SF. Migration of PMNs could be reduced by neutralization of CXCL16 activity in gouty SF. For in vivo analyses, fluorescent dye–tagged PMNs were injected intravenously into SCID mice while, simultaneously, diluted gouty SF containing CXCL16, or depleted of CXCL16 by antibody blocking, was administered intragraft. In addition, the receptor for CXCL16, CXCR6, was inhibited by incubating PMNs with a neutralizing anti-CXCR6 antibody prior to injection into the mouse chimeras. Recruitment of PMNs to the gouty SF–injected normal human ST was then examined in this SCID mouse chimera system.



Results

CXCL16 concentrations were highly elevated in gouty SF, and PMNs were observed to migrate in response to CXCL16 in vitro. Normal human ST–SCID mouse chimeras injected intragraft with gouty SF that had been depleted of CXCL16 during PMN transfer showed a significant reduction of 50% in PMN recruitment to engrafted tissue as compared with that after administration of sham-depleted gouty SF. Similar findings were achieved when PMNs were incubated with a neutralizing anti-CXCR6 antibody before injection into chimeras.



Conclusion

Overall, the results of this study outline the effectiveness of the human–SCID mouse chimera system as a viable animal model of gout, serving to identify the primary function of CXCL16 as a significant mediator of in vivo recruitment of PMNs to gouty SF.

/pdf/expression-and-function-of-cxcl16-in-a-novel-model-of-gout-46jizw16s2.pdf

Expression and function of CXCL16 in a novel model of gout.

/pdf/a-novel-role-for-monosodium-urate-monohydrate-crystals-and-2gspnemnbm.pdf

A novel role for monosodium urate monohydrate crystals and gouty synovial fluids in monocyte migration in gout

Rationale
Angiogenesis plays an important role in wound healing and tumor growth. Fucosyltransferases synthesize fucosylated glycans and may play a major role in vascular biology.

A novel role for inducible Fut2 in angiogenesis

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Papers

Expression and function of CXCL16 in a novel model of gout.

A novel role for monosodium urate monohydrate crystals and gouty synovial fluids in monocyte migration in gout

A novel role for inducible Fut2 in angiogenesis