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Background Changes in protein glycosylation are widely observed in tumor cells. N -glycan branching through adding β1,6-linked N -acetylglucosamine (β1,6-GlcNAc) to an α1,6-linked mannose, which is catalyzed by the N -acetylglucosaminyltransferase V (MGAT5 or GnT-V), is one of the most frequently observed tumor-associated glycan structure formed. Increased levels of this branching structure play a pro-tumoral role in various ways, for example, through the stabilization of growth factor receptors, the destabilization of intercellular adhesion, or the acquisition of a migratory phenotype. Conclusion In this review, we provide an updated and comprehensive summary of the physiological and pathophysiological roles of MGAT5 and β1,6-GlcNAc branched N -glycans, including their regulatory mechanisms. Specific emphasis is given to the role of MGAT5 and β1,6-GlcNAc branched N -glycans in cellular mechanisms that contribute to the development and progression of solid tumors. We also provide insight into possible future clinical implications, such as the use of MGAT5 as a prognostic biomarker.

Background Chronic obstructive pulmonary disease (COPD) is characterized by incomplete reversible airflow limitation and chronic inflammatory response lesions. This study mainly explored whether FGFR2 and MGAT5 polymorphisms affected the risk of COPD in the Chinese people. Methods Five variants in FGFR2 and MGAT5 were chosen and genotyped using Agena MassARRAY platform from 315 COPD patients and 314 healthy controls. The correlation of FGFR2 and MGAT5 with COPD susceptibility was evaluated with odds ratio (OR) and 95% confidence interval (CI) via logistic regression. Results We found rs2420915 enhanced the risk of COPD, while rs6430491, rs2593704 reduced the susceptibility of COPD ( p  < 0.05). Rs2420915 could promote the incidence of COPD in the elderly and nonsmokers. Rs1907240 and rs2257129 also increased the susceptibility to COPD in nonsmokers ( p  < 0.05). MGAT5- rs2593704 played a protective role in COPD development in different subgroups (age ≤ 70, male, smokers, and individuals with BMI ≤ 24 kg/m 2 ). Meanwhile, rs6430491 was linked with a lower risk of COPD in nonsmoking and BMI ≤ 24 kg/m 2 subgroups. Conclusions We concluded that FGFR2 and MGAT5 genetic polymorphisms are correlated with the risk of COPD in the Chinese people. These data underscored the important role of FGFR2 and MGAT5 gene in the occurrence of COPD and provided new biomarkers for COPD treatment. Trial registration : NA.

Background Glioblastomas stem-like cells (GSCs) by invading the brain parenchyma, remains after resection and radiotherapy and the tumoral microenvironment become stiffer. GSC invasion is reported as stiffness sensitive and associated with altered N-glycosylation pattern. Glycocalyx thickness modulates integrins mechanosensing, but details remain elusive and glycosylation enzymes involved are unknown. Here, we studied the association between matrix stiffness modulation, GSC migration and MGAT5 induced N-glycosylation in fibrillar 3D context. Method To mimic the extracellular matrix fibrillar microenvironments, we designed 3D-ex-polyacrylonitrile nanofibers scaffolds (NFS) with adjustable stiffnesses by loading multiwall carbon nanotubes (MWCNT). GSCs neurosphere were plated on NFSs, allowing GSCs migration and MGAT5 was deleted using CRISPR-Cas9. Results We found that migration of GSCs was maximum at 166 kPa. Migration rate was correlated with cell shape, expression and maturation of focal adhesion (FA), Epithelial to Mesenchymal Transition (EMT) proteins and (β1,6) branched N-glycan binding, galectin-3. Mutation of MGAT5 in GSC inhibited N-glycans (β1–6) branching, suppressed the stiffness dependence of migration on 166 kPa NFS as well as the associated FA and EMT protein expression. Conclusion MGAT5 catalysing multibranched N-glycans is a critical regulators of stiffness induced invasion and GSCs mechanotransduction, underpinning MGAT5 as a serious target to treat cancer.

Background Abnormal glycosylation modification is closely related to the development and metastasis of cancers. As a carcinogen by the International Agency for Research on Cancer (IARC) of the WHO, areca nut lacked of combined effect’ study with genetic factors related to lung cancer. The aim of this study was to investigate the combined effect of polymorphisms of glycosyltransferase family genes and behavioral factors on the susceptibility of lung cancer. Methods A case‒control study was conducted in Hainan, which included 428 patients with lung cancer and 428 cancer-free controls. Six single-nucleotide polymorphisms (SNPs) (FUT2 rs1047781, rs601338, FUT3 rs28362459, rs3745635, ST6Gal-I rs2239611 and MGAT5 rs34944508) were detected by the MassARRAY System. The association between these SNPs and the risk of lung cancer, clinicopathological characteristics, and combined effect of behavioral factors (areca nuts, cigarettes, alcohol) and genotypes on lung cancer were estimated using by logistic regression analysis. Results In this study, individuals with AA genotype in ST6Gal-I rs2239611 significantly increased lung cancer risk (OR adj  = 2.077; 95%CI:1.191–3.624; P adj  = 0.010), particularly in smokers ( P adj  = 0.038) and alcohol consumers ( P adj  = 0.049). FUT2 rs1047781 was associated with clinical stage ( P adj  = 0.047) and lymph node metastasis ( P adj  = 0.014). Significant gene-environment interactions were observed between behavioral factors (cigarette smoking, alcohol drinking, and betel quid chewing) and both FUT2 rs1047781 ( P adj  = 0.013) and ST6Gal-I rs2239611 ( P adj  = 0.047), collectively elevating lung cancer risk. Conclusion ST6Gal-I rs2239611 was a potential genetic biomarker for lung cancer. Areca nut chewing, cigarette smoking, alcohol drinking interacts with glycosyltransferase gene polymorphisms (FUT2 rs1047781 and ST6Gal-I rs2239611), increasing lung cancer risk—a novel finding given the lack of prior studies on this combination.

Galectins are β-galactoside-binding lectins consisting of 15 members in mammals. Galectin-1,-3,-4,-8, and -9 are predominantly expressed in the central nervous system (CNS) and regulate various physiological and pathological events. This review summarizes the current knowledge of the cellular expression and role of galectins in the CNS, and discusses their functions in neurite outgrowth, myelination, and neural stem/progenitor cell niches, as well as in ischemic/hypoxic/traumatic injuries and neurodegenerative diseases such as multiple sclerosis. Galectins are expressed in both neurons and glial cells. Galectin-1 is mainly expressed in motoneurons, whereas galectin-3-positive neurons are broadly distributed throughout the brain, especially in the hypothalamus, indicating its function in the regulation of homeostasis, stress response, and the endocrine/autonomic system. Astrocytes predominantly contain galectin-1, and galectin-3 and−9 are upregulated along with its activation. Activated, but not resting, microglia contain galectin-3, supporting its phagocytic activity. Galectin-1,−3, and -4 are characteristically expressed during oligodendrocyte differentiation. Galectin-3 from microglia promotes oligodendrocyte differentiation and myelination, while galectin-1 and axonal galectin-4 suppress its differentiation and myelination. Galectin-1- and- 3-positive cells are involved in neural stem cell niche formation in the subventricular zone and hippocampal dentate gyrus, and the migration of newly generated neurons and glial cells to the olfactory bulb or damaged lesions. In neurodegenerative diseases, galectin-1,-8, and -9 have neuroprotective and anti-inflammatory activities. Galectin-3 facilitates pro-inflammatory action; however, it also plays an important role during the recovery period. Several ligand glycoconjugates have been identified so far such as laminin, integrins, neural cell adhesion molecule L1, sulfatide, neuropilin-1/plexinA4 receptor complex, triggering receptor on myeloid cells 2, and T cell immunoglobulin and mucin domain. N -glycan branching on lymphocytes and oligodendroglial progenitors mediated by β1,6- N -acetylglucosaminyltransferase V (Mgat5/GnTV) influences galectin-binding, modulating inflammatory responses and remyelination in neurodegenerative diseases. De-sulfated galactosaminoglycans such as keratan sulfate are potential ligands for galectins, especially galectin-3, regulating neural regeneration. Galectins have multitudinous functions depending on cell type and context as well as post-translational modifications, including oxidization, phosphorylation, S-nitrosylation, and cleavage, but there should be certain rules in the expression patterns of galectins and their ligand glycoconjugates, possibly related to glucose metabolism in cells.

Complex asparagine-linked glycosylation plays key roles in cellular functions, including cellular signaling, protein stability, and immune response. Previously, we characterized the appearance of a complex asparagine-linked glycosylated form of lysosome-associated membrane protein 1 (LAMP1) in the cerebellum of Npc1−/− mice. This LAMP1 form was found on activated microglia, and its appearance correlated both spatially and temporally with cerebellar Purkinje neuron loss. To test the importance of complex asparagine-linked glycosylation in NPC1 pathology, we generated NPC1 knock-out mice deficient in MGAT5, a key Golgi-resident glycosyl transferase involved in complex asparagine-linked glycosylation. Our results show that Mgat5−/−:Npc1−/− mice were smaller than Mgat5+/+:Npc1−/− mice, and exhibited earlier NPC1 disease onset and reduced lifespan. Western blot and lectin binding analyses of cerebellar extracts confirmed the reduction in complex asparagine-linked glycosylation, and the absence of the hyper-glycosylated LAMP1 previously observed. Western blot analysis of cerebellar extracts demonstrated reduced calbindin staining in Mgat5−/−:Npc1−/− mice compared to Mgat5+/+:Npc1−/− mutant mice, and immunofluorescent staining of cerebellar sections indicated decreased levels of Purkinje neurons and increased astrogliosis in Mgat5−/−:Npc1−/− mice. Our results suggest that reduced asparagine-linked glycosylation increases NPC1 disease severity in mice, and leads to the hypothesis that mutations in genes involved in asparagine-linked glycosylation may contribute to disease severity progression in individuals with NPC1. To examine this with respect to MGAT5, we analyzed 111 NPC1 patients for two MGAT5 SNPs associated with multiple sclerosis; however, we did not identify an association with NPC1 phenotypic severity.

Gastric cancer is a common malignant tumor with high morbidity and mortality. The present study aimed to investigate the role of the immunoglobulin superfamily containing leucine-rich repeat (ISLR) gene in gastric cancer and examine whether ISLR could interact with N-acetylglucosaminyltransferase V (MGAT5) to affect the malignant progression of gastric cancer. The expression of ISLR and MGAT5 in human normal gastric epithelial cells and human gastric cancer cells, and the transfection efficiency of ISLR interference plasmids and MGAT5 overexpression plasmids were all detected by reverse transcription-quantitative PCR (RT-qPCR) and western blot. The viability, proliferation, migration and invasion, and epithelial-mesenchymal transition (EMT) of gastric cancer cells after indicated transfection were detected by Cell counting kit-8 (CCK-8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, wound healing assay, and transwell assay. The interaction between ISLR and MGAT5 was confirmed by co-immunoprecipitation. The expression of proteins related to migration, invasion, and EMT was detected by immunofluorescence and western blot. As a result, ISLR was highly expressed in gastric cancer and was associated with poor prognosis. Interference with ISLR inhibited the viability, proliferation, migration, invasion, and EMT of gastric cancer cells. ISLR interacted with MGAT5 in gastric cancer cells. MGAT5 overexpression weakened the effects of ISLR knockdown on suppressing the viability, proliferation, migration, invasion, and EMT of gastric cancer cells. ISLR interacted with MGAT5 to promote the malignant progression of gastric cancer.

Increasing evidence supports the crucial role of Epithelial-Mesenchymal Transition (EMT) in cancer invasion and metastasis. N-acetylglucosaminyltransferase V (MGAT5), which is associated with multiantenna glycosylation, can contribute to tumorigenesis, yet its specific role in promoting colorectal cancer (CRC) metastasis remains unclear. Bioinformatics analysis of CRC datasets revealed that elevated MGAT5 expression was associated with EMT and a poor prognosis. In vitro experiments confirmed the pivotal role of MGAT5 as an EMT regulator in CRC cells. MGAT5 overexpression stimulated cell proliferation and migration, while MGAT5 knockdown had the opposite effect. Mechanistically, MGAT5 promoted EMT through multiantenna glycosylation of ZO-1, promoting its ubiquitination and reducing its expression. Clinically, MGAT5 upregulation in the CRC TMA correlated negatively with ZO-1 expression, which is indicative of malignancy and a poor prognosis. This study revealed that MGAT5 promotes EMT in CRC via interactions between multiple antenna glycosylation products and ZO-1 ubiquitination/degradation, indicating that MGAT5 could serve as a promising therapeutic target for CRC. Graphical Abstract

Golgi β1,6N-acetylglucosaminyltransferase V (MGAT5) is required in the biosynthesis of β1,6GlcNAc-branched N-linked glycans attached to cell surface and secreted glycoproteins. Amounts of MGAT5 glycan products are commonly increased in malignancies, and correlate with disease progression. To study the functions of these N-glycans in development and disease, we generated mice deficient in Mgat5 by targeted gene mutation. These Mgat5 −/− mice lacked Mgat5 products and appeared normal, but differed in their responses to certain extrinsic conditions. Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene was considerably less in Mgat5 −/− mice than in transgenic littermates expressing Mgat5. Furthermore, Mgat5 glycan products stimulated membrane ruffling and phosphatidylinositol 3 kinase–protein kinase B activation, fueling a positive feedback loop that amplified oncogene signaling and tumor growth in vivo . Our results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis.

Breast cancer is a global health problem. It is an age-dependent disease, but cases of early-onset breast cancer (eBC) are gradually increasing. There are many unresolved questions regarding eBC risk factors, mechanisms of development and screening. Only 10% of eBC cases are due to mutations in the BRCA1/BRCA2 genes, and 90% have a more complex genetic background. This poses a significant challenge to timely cancer detection in young women and highlights the need for research and awareness. Therefore, identifying genetic risk factors for eBC is essential to solving these problems. This study represents an association analysis of 144 eBC cases and 163 control participants to identify genetic markers associated with eBC risks in Kazakh women. We performed a two-stage approach in association analysis to assess genetic predisposition to eBC. First-stage genome-wide association analysis revealed two risk intronic loci in the CHI3L2 gene (p = 5.2 × 10−6) and MGAT5 gene (p = 8.4 × 10−6). Second-stage exonic polymorphisms haplotype analysis showed significant risks for seven haplotypes (p < 9.4 × 10−4). These results point to the importance of studying medium- and low-penetrant genetic markers in their haplotype combinations for a detailed understanding of the role of detected genetic markers in eBC development and prediction.