title: Intrinsic hepatocyte dedifferentiation is accompanied by upregulation of mesenchymal markers, protein sialylation and core alpha 1,6 linked fucosylation.
abstract: Alterations in N-linked glycosylation have long been associated with cancer but for the most part, the reasons why have remained poorly understood. Here we show that increased core fucosylation is associated with de-differentiation of primary hepatocytes and with the appearance of markers indicative of a transition of cells from an epithelial to a mesenchymal state. This increase in core fucosylation was associated with increased levels of two enzymes involved in α-1,6 linked fucosylation, GDP-mannose 4, 6-dehydratase (Gmds) and to a lesser extent fucosyltransferase 8 (Fut8). In addition, the activation of cancer-associated cellular signaling pathways in primary rat hepatocytes can increase core fucosylation and induce additional glycoform alterations on hepatocyte proteins. Specifically, we show that increased levels of protein sialylation and α-1,6-linked core fucosylation are observed following activation of the β-catenin pathway. Activation of the Akt signaling pathway or induction of hypoxia also results in increased levels of fucosylation and sialylation. We believe that this knowledge will help in the better understanding of the genetic factors associated with altered glycosylation and may allow for the development of more clinically relevant biomarkers.
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Comunale
authors.affiliation: Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Molecular and Cellular Biology and Genetics Graduate Program, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Rawat
authors.affiliation: Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Molecular and Cellular Biology and Genetics Graduate Program, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Casciano
authors.affiliation: Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Microbiology and Immunology Graduate Program, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Lamontagne
authors.affiliation: Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Microbiology and Immunology Graduate Program, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Harmin
authors.initials: H
authors.lastname: Herrera
authors.affiliation: Graduate School of Biomedical Sciences and Professional Studies, Drexel University College of Medicine, Microbiology and Immunology Graduate Program, 2900 Queen Lane, Philadelphia, PA 19129, USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Ramanathan
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Betesh
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Mengjun
authors.initials: M
authors.lastname: Wang
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, 245 N. 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Norton
authors.affiliation: Drexel University College of Medicine, Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, 245 North 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Steel
authors.affiliation: Drexel University College of Medicine, Department of Biochemistry and Molecular Biology, 245 N. 15th Street, Philadelphia, PA 19102, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bouchard
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000473:pathology*; D054337:Cell Dedifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D022781:Hepatocytes / Q000166:cytology; D006836:Hydro-Lyases / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008113:Liver Neoplasms / Q000175:diagnosis / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D051057:Proto-Oncogene Proteins c-akt; D006836:Hydro-Lyases; C044971:GDPmannose 4,6-dehydratase