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1. O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in myofibroblasts

Author

Ninon Very, Clémence Boulet, Céline Gheeraert, Alexandre Berthier, Manuel Johanns, Mohamed Bou Saleh, Loïc Guille, Fabrice Bray, Jean-Marc Strub, Marie Bobowski-Gerard, Francesco P. Zummo, Emmanuelle Vallez, Olivier Molendi-Coste, Eloise Woitrain, Sarah Cianférani, David Montaigne, Line Carolle Ntandja-Wandji, Laurent Dubuquoy, Julie Dubois-Chevalier, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute

Subjects
Cytology, QH573-671
Abstract

Abstract Tissue injury causes activation of mesenchymal lineage cells into wound-repairing myofibroblasts (MFs), whose uncontrolled activity ultimately leads to fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, we report that the metabolic sensor post-translational modification O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) is increased and required for myofibroblastic activation. Inhibition of protein O-GlcNAcylation impairs archetypal myofibloblast cellular activities including extracellular matrix gene expression and collagen secretion/deposition as defined in vitro and using ex vivo and in vivo murine liver injury models. Mechanistically, a multi-omics approach combining proteomic, epigenomic, and transcriptomic data mining revealed that O-GlcNAcylation controls the MF transcriptional program by targeting the transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes-associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O-GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of the MF transcriptional regulatory landscape. We found that this involves O-GlcNAcylation of BNC2 at Thr455 and Ser490 and of TEAD4 at Ser69 and Ser99. Altogether, this study unravels protein O-GlcNAcylation as a key determinant of myofibroblastic activation and identifies its inhibition as an avenue to intervene with fibrogenic processes.

Published
2024
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2. Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis

Author

Marie Bobowski-Gerard, Clémence Boulet, Francesco P. Zummo, Julie Dubois-Chevalier, Céline Gheeraert, Mohamed Bou Saleh, Jean-Marc Strub, Amaury Farce, Maheul Ploton, Loïc Guille, Jimmy Vandel, Antonino Bongiovanni, Ninon Very, Eloïse Woitrain, Audrey Deprince, Fanny Lalloyer, Eric Bauge, Lise Ferri, Line-Carolle Ntandja-Wandji, Alexia K. Cotte, Corinne Grangette, Emmanuelle Vallez, Sarah Cianférani, Violeta Raverdy, Robert Caiazzo, Viviane Gnemmi, Emmanuelle Leteurtre, Benoit Pourcet, Réjane Paumelle, Kim Ravnskjaer, Guillaume Lassailly, Joel T. Haas, Philippe Mathurin, François Pattou, Laurent Dubuquoy, Bart Staels, Philippe Lefebvre, and Jérôme Eeckhoute

Subjects
Science
Abstract

Myofibroblasts contribute to the development of liver fibrosis. Here, the authors report that the transcription factor Basonuclin 2 (BNC2) integrates fibrogenic signals and drives myofibroblastic transcriptional activation in liver fibrosis.

Published
2022
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3. Severe SARS‐CoV‐2 patients develop a higher specific T‐cell response

Author

Julie Demaret, Guillaume Lefèvre, Fanny Vuotto, Jacques Trauet, Alain Duhamel, Julien Labreuche, Pauline Varlet, Arnaud Dendooven, Sarah Stabler, Benoit Gachet, Jules Bauer, Brigitte Prevost, Laurence Bocket, Enagnon Kazali Alidjinou, Marc Lambert, Cécile Yelnik, Bertrand Meresse, Laurent Dubuquoy, David Launay, Sylvain Dubucquoi, David Montaigne, Eloise Woitrain, François Maggiotto, Mohamed Bou Saleh, Isabelle Top, Vincent Elsermans, Emmanuelle Jeanpierre, Annabelle Dupont, Sophie Susen, Thierry Brousseau, Julien Poissy, Karine Faure, Myriam Labalette, and the Lille Covid Research Network (LICORNE)

Subjects
ELISpot, SARS‐CoV‐2, T cells, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Objectives Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is crucial for studying long‐term immunity and vaccine strategies. We quantified IFNγ‐secreting T cells reactive against the main viral SARS‐CoV‐2 antigens using a standardised enzyme‐linked immunospot assay (ELISpot). Methods Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T‐CoV‐Spot assay, we assessed T‐cell and antibody responses in mild, moderate and severe SARS‐CoV‐2 patients and in control samples collected before the outbreak. Results Specific T cells were assessed in 60 consecutive patients (mild, n = 26; moderate, n = 10; and severe patients, n = 24) during their follow‐up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in n = 60 (100%), n = 56 (93.3%), n = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T‐CoV‐Spot assay showed a specificity of 96.7% (95% CI, 88.5–99.6%) and a specificity of 90.3% (75.2–98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti‐S1 and anti‐RBD serum antibodies. Conclusion IFNγ T‐CoV‐Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long‐lived memory T‐cell response after vaccination. Our study demonstrates that SARS‐CoV‐2 patients developing a severe disease achieve a higher adaptive immune response.

Published
2020
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4. Loss of hepatocyte identity following aberrant YAP activation: a key mechanism in alcoholic hepatitis

Author

Julie Dubois-Chevalier, Guillaume Lassailly, François Maggiotto, Line Carolle Ntandja-Wandji, Massih Ningarhari, Philippe Mathurin, Sébastien Dharancy, Pau Sancho-Bru, Laurent Dubuquoy, Emmanuel Boleslawski, Anne Corlu, Josepmaria Argemi, Florent Artru, Alexandre Louvet, Jérôme Eeckhoute, Emilie Anglo, Mohamed Bou Saleh, Stéphanie Truant, Viviane Gnemmi, Ramon Bataller, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Sequencing was performed by the GenomEast platform, a member of the 'France Génomique' consortium (ANR-10-INBS-0009)., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors acknowledge funding from the National Institute on Alcohol Abuse and Alcoholism (NIAAA-->/NIH, grant 1U01AA021908), Association Française pour l'Etude du Foie, Institut national de la santé et de la recherche médicale (INSERM), CHU de Lille and Région Haut de France. Work at INSERM U1011 was supported by grants from the Fondation pour la Recherche Médicale (Equipe labellisée, DEQ20150331724), 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46) and European Commission. PS-B was supported by Fondo de Investigación Sanitaria Carlos III (FIS), co-financed by Fondo Europeo de Desarrollo Regional, Unión Europea, 'Una manera de hacer Europa' (FIS PI17/00673, and from the NIAAA grant 1U01AA021908-01-33490., Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Nutrition, Métabolismes et Cancer [NuMeCan], University of Pittsburgh [PITT], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Université de Lille, Inserm, CHU Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Université de Lille, LillOA, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID

Subjects
0301 basic medicine, MST1, Alcoholic hepatitis, Hepatocyte, Hippo/YAP, Regeneration, Transdifferentiation, 03 medical and health sciences, Mice, [SCCO]Cognitive science, 0302 clinical medicine, Downregulation and upregulation, medicine, Animals, Hepatocyte differentiation, Hippo signaling pathway, Hepatology, Chemistry, Hepatitis, Alcoholic, YAP-Signaling Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SCCO] Cognitive science, medicine.disease, Liver regeneration, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Cancer research, Hepatocytes, 030211 gastroenterology & hepatology, Female, France
Abstract

International audience; Background & AimsAlcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, because understanding of the molecular drivers leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration.MethodThe Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcoholic cirrhosis and in control livers, using RNA-Seq, real-time PCR, Western blot, immunohistochemistry (IHC) and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (CCl4) after hepatocyte transduction of YAPS127A.ResultsIn AH samples RNA-Seq analysis and IHC of total liver and microdissected hepatocytes revealed marked down-regulation of Hippo shown by lower MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, treatment of abnormal hepatocytes from AH patients with a YAP inhibitor restored the mature hepatocyte phenotype. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered using YAPS127A after CCl4 intoxication.ConclusionAberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH.Lay summaryAlcoholic hepatitis (AH) is characterized by inflammation and a life-threatening alteration of liver regeneration by mechanisms that have not been identified. We show that AH livers are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of the transcription co-factor YAP in hepatocytes. YAP activation in hepatocytes leads to their transdifferentiation towards a biliary phenotype associated with inflammation as well as a regeneration defect. YAP inhibition reverts this hepatocyte defect and appears to be an original therapeutic strategy of regenerative treatment for AH.

Published
2021

5. Severe SARS‐CoV‐2 patients develop a higher specific T‐cell response

Author

Enagnon Kazali Alidjinou, Karine Faure, Isabelle Top, Alain Duhamel, Jacques Trauet, Emmanuelle Jeanpierre, Julien Poissy, Bertrand Meresse, Benoit Gachet, Fanny Vuotto, Pauline Varlet, Guillaume Lefèvre, Sarah Stabler, Jules Bauer, C. Yelnik, François Maggiotto, Vincent Elsermans, Arnaud Dendooven, Julien Labreuche, Sophie Susen, Mohamed Bou Saleh, David Launay, Thierry Brousseau, Sylvain Dubucquoi, Brigitte Prevost, Eloise Woitrain, Laurence Bocket, Marc Lambert, Julie Demaret, David Montaigne, Annabelle Dupont, Myriam Labalette, Laurent Dubuquoy, Institut d'Immunologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Pathogenèse virale du diabète de type 1 - ULR 3610 (Laboratoire de Virologie), Centre de référence des maladies auto-immunes systémiques rares du Nord et Nord Ouest [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), I-SITE ULNE. Grant Number: ANR-16-IDEX-0004 ULNE, ANR-16-IDEX-0004,ULNE,ULNE(2016), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, LillOA, ULNE - - ULNE2016 - ANR-16-IDEX-0004 - IDEX - VALID, Université de Lille, CNRS, Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)], Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Pathogenèse virale du diabète de type 1 - ULR 3610, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017, and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD)

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, Immunology, ELISpot, T cells, SARS‐CoV‐2, 03 medical and health sciences, 0302 clinical medicine, Antigen, Immunity, Interquartile range, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Medicine, 030212 general & internal medicine, General Nursing, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, business.industry, SARS-CoV-2, ELISPOT, Outbreak, Original Articles, Acquired immune system, 3. Good health, Vaccination, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Original Article, Antibody, business, lcsh:RC581-607
Abstract

Objectives Assessment of the adaptive immune response against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is crucial for studying long‐term immunity and vaccine strategies. We quantified IFNγ‐secreting T cells reactive against the main viral SARS‐CoV‐2 antigens using a standardised enzyme‐linked immunospot assay (ELISpot). Methods Overlapping peptide pools built from the sequences of M, N and S viral proteins and a mix (MNS) were used as antigens. Using IFNγ T‐CoV‐Spot assay, we assessed T‐cell and antibody responses in mild, moderate and severe SARS‐CoV‐2 patients and in control samples collected before the outbreak. Results Specific T cells were assessed in 60 consecutive patients (mild, n = 26; moderate, n = 10; and severe patients, n = 24) during their follow‐up (median time from symptom onset [interquartile range]: 36 days [28;53]). T cells against M, N and S peptide pools were detected in n = 60 (100%), n = 56 (93.3%), n = 55 patients (91.7%), respectively. Using the MNS mix, IFNγ T‐CoV‐Spot assay showed a specificity of 96.7% (95% CI, 88.5–99.6%) and a specificity of 90.3% (75.2–98.0%). The frequency of reactive T cells observed with M, S and MNS mix pools correlated with severity and with levels of anti‐S1 and anti‐RBD serum antibodies. Conclusion IFNγ T‐CoV‐Spot assay is a reliable method to explore specific T cells in large cohorts of patients. This test may become a useful tool to assess the long‐lived memory T‐cell response after vaccination. Our study demonstrates that SARS‐CoV‐2 patients developing a severe disease achieve a higher adaptive immune response., We quantified IFNg‐secreting T cells reactive against the M, N and S viral SARS‐CoV‐2 proteins using a standardized enzyme‐linked immunospot assay in 60 patients. The frequency of reactive T cells correlated with severity, and with levels of anti‐S1 and anti‐RBD (receptor binding domain) serum antibodies, demonstrating a higher adaptive immune response after developing a more severe disease. IFNg T‐CoV‐Spot assay may also become a useful tool to assess the long‐lived memory T cell response after vaccination.

Published
2020

6. Tspan15 Is a New Stemness-Related Marker in Hepatocellular Carcinoma

Author

Taous Ait Saadi, François Le Naour, Nazha Sidahmed-Adrar, Philippe Mauduit, Nassima Benzoubir, Catherine Guettier, Mohamed Bou Saleh, Christophe Desterke, Jean-François Ottavi, Pathogénèse et traitement de l'hépatite fulminante et du cancer du foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Réponses cellulaires au microenvironnement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Proteomics, Carcinoma, Hepatocellular, Tetraspanins, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Biochemistry, 03 medical and health sciences, ADAM10 Protein, Tetraspanin, Growth factor receptor, Cancer stem cell, medicine, Biomarkers, Tumor, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Cell growth, Growth factor, 030302 biochemistry & molecular biology, Cell Membrane, Liver Neoplasms, Connective Tissue Growth Factor, Membrane Proteins, Hep G2 Cells, 3. Good health, CTGF, Gene Expression Regulation, Neoplastic, Tumor progression, Cancer research, Neoplastic Stem Cells, Amyloid Precursor Protein Secretases
Abstract

Hepatocellular carcinoma (HCC) is the second cause of cancer-related deaths worldwide. A clearer understanding of the molecular mechanisms underlying tumor growth and invasiveness remains crucial for developing new therapies. Here, the expression of tetraspanins, a family of plasma membrane organizers involved in tumor progression, has been addressed. Integrative approaches combining transcriptomics and bioinformatics allow demonstrating the induced and heterogeneous expression of Tspan15 in HCC. Tspan15 positive tumors exhibit signatures related to hepatic progenitor cells as well as recurrence of cancer. Immunohistochemistry experiments confirm Tspan15 expression in the subset of HCC expressing stemness-related markers such as EpCAM and Cytokeratin-19. Functional networks reveal that most of these genes expressed in correlation to Tspan15 support cell proliferation. Furthermore, Tspan15 overexpression in the hepatoma cell line HepG2 significantly increases cell proliferation. A quantitative proteomic analysis of the secretome reveals a higher abundance of the protein connective tissue growth factor (CTGF), a pleiotropic matricellular signaling protein. Proteomic profiling of Tspan15 complexes allows identifying numerous membrane proteins including several growth factor receptors. Finally, Tspan15 increases ERK1/2 phosphorylation that directly controls CTGF expression and secretion. In conclusion, Tspan15 is a new stemness-related marker in HCC which exhibits high potential of tumor growth and recurrence.

Published
2019

7. Nucleotide-binding oligomerization domain 1 (NOD1) modulates liver ischemia reperfusion through the expression adhesion molecules

Author

Sébastien Dharancy, Benjamin Bertin, François Maggiotto, Patrice Maboudou, Florent Artru, Mohamed Bou Saleh, Guillaume Lassailly, Céline Gheeraert, Philippe Mathurin, Rodolphe Carpentier, Didier Betbeder, Emilie Gantier, Laurent Dubuquoy, Natascha Leleu-Chavain, Viviane Gnemmi, Massih Ningarhari, Alexandre Louvet, Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, CHU Lille, Inserm, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Lille Inflammation Research International Center - U 995 [LIRIC], and Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]

Subjects
0301 basic medicine, Agonist, Necrosis, medicine.drug_class, Neutrophils, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Vascular Cell Adhesion Molecule-1, Liver transplantation, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Lactate dehydrogenase, Nod1 Signaling Adaptor Protein, NOD1, medicine, Animals, Humans, Liver injury, Hepatology, Cell adhesion molecule, medicine.disease, Intercellular Adhesion Molecule-1, Molecular biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, body regions, 030104 developmental biology, medicine.anatomical_structure, chemistry, Liver, Hepatocyte, Reperfusion Injury, 030211 gastroenterology & hepatology, medicine.symptom, Signal Transduction
Abstract

Background & Aims In liver transplantation, organ shortage leads to the use of marginal grafts that are more susceptible to ischemia–reperfusion (IR) injury. We identified nucleotide-binding oligomerization domain 1 (NOD1) as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in IR. Herein, we aimed to elucidate the role of NOD1 in IR injury, particularly focusing on its effects on the endothelium and hepatocytes. Method Nod1 WT and KO mice were treated with NOD1 agonists and subjected to liver IR. Expression of adhesion molecules was analyzed in total liver, isolated hepatocytes and endothelial cells. Interactions between PMNs and hepatocytes were studied in an ex vivo co-culture model using electron microscopy and lactate dehydrogenase levels. We generated NOD1 antagonist-loaded nanoparticles (np ALINO). Results NOD1 agonist treatment increased liver injury, PMN tissue infiltration and upregulated ICAM-1 and VCAM-1 expression 20 hours after reperfusion. NOD1 agonist treatment without IR increased expression of adhesion molecules (ICAM-1, VCAM-1) in total liver and more particularly in WT hepatocytes, but not in Nod1 KO hepatocytes. This induction is dependent of p38 and ERK signaling pathways. Compared to untreated hepatocytes, a NOD1 agonist markedly increased hepatocyte lysis in co-culture with PMNs as shown by the increase of lactate dehydrogenase in supernatants. Interaction between hepatocytes and PMNs was confirmed by electron microscopy. In a mouse model of liver IR, treatment with np ALINO significantly reduced the area of necrosis, aminotransferase levels and ICAM-1 expression. Conclusion NOD1 regulates liver IR injury through induction of adhesion molecules and modulation of hepatocyte-PMN interactions. NOD1 antagonist-loaded nanoparticles reduced liver IR injury and provide a potential approach to prevent IR, especially in the context of liver transplantation. Lay summary Nucleotide-binding oligomerization domain 1 (NOD1) is as an important modulator of polymorphonuclear neutrophil (PMN)-induced liver injury, which occurs in ischemia-reperfusion. Here, we show that the NOD1 pathway targets liver adhesion molecule expression on the endothelium and on hepatocytes through p38 and ERK signaling pathways. The early increase of adhesion molecule expression after reperfusion emphasizes the importance of adhesion molecules in liver injury. In this study we generated nanoparticles loaded with NOD1 antagonist. These nanoparticles reduced liver necrosis by reducing PMN liver infiltration and adhesion molecule expression.

Published
2019

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