title: Altered β1,6-GlcNAc branched N-glycans impair TGF-β-mediated epithelial-to-mesenchymal transition through Smad signalling pathway in human lung cancer.
abstract: The change of oligosaccharide structure has been revealed to be crucial for glycoproteins' biological functions and cell biological characteristics. N-acetylglucosaminy transferase V (GnT-V), a key enzyme catalysing the reaction of adding β1, 6-N-acetylglucosamine (GlcNAc) on asparagine-linked oligosaccharides of cell proteins, has been implicated to a metastastic-promoting oncoprotein in some carcinomas. However, this correlation might not be subjected to all types of cancers, for example, in non-small cell lung cancers, low level of GnT-V expression is associated with relatively short survival time and poor prognosis. To explain the role of GnT-V in lung cancer progression, we studied the association of GnT-V expression with lung cancer EMT behaviour. We found that GnT-V expression was correlated with epithelial marker positively and mesenchymal marker negatively. GnT-V levels, as well as β1,6-GlcNAc branched N-glycans, were strongly reduced in TGF-β1-induced EMT of human lung adenocarcinoma A549 cells. Further studies showed that suppression of β1,6-GlcNAc branched N-glycans by inhibitor or GnT-V silencing in A549 cells could promote TGF-β1-induced EMT-like changes, cell migration and invasion. Meanwhile, overexpression of GnT-V impaired TGF-β1-induced EMT, migration and invasion. It suggests that GnT-V suppresses the EMT process of lung cancer cells through inhibiting the TGF-β/Smad signalling and its downstream transcription factors in a GnT-V catalytic activity-dependent manner. Taken together, the present study reveals a novel mechanism of GnT-V as a suppressor of both EMT and invasion in human lung cancer cells, which may be useful for fully understanding N-glycan's biological roles in lung cancer progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Glycoconjugate Research, Ministry of Health, Shanghai, China; Key Laboratory of Molecular Medicine, Ministry of Education, Shanghai, China; Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Haineng
authors.initials: H
authors.lastname: Xu
authors.forename: Kun
authors.initials: K
authors.lastname: Fan
authors.forename: Xijun
authors.initials: X
authors.lastname: Liu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Qi
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Peng
authors.initials: P
authors.lastname: Yin
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.forename: Zengxia
authors.initials: Z
authors.lastname: Li
authors.forename: Xiliang
authors.initials: X
authors.lastname: Zha
mesh_terms: D000117:Acetylglucosamine / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D011134:Polysaccharides; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D008156:Luciferases; D017351:N-Acetylglucosaminyltransferases; D000117:Acetylglucosamine
keywords: EMT; GnT-V; N-glycans; TGF-β1; lung cancer