34 results on '"I. Van Seuningen"'
Search Results
2. Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells
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Michael Perrais, Audrey Vincent, I. Van Seuningen, Jean-Luc Desseyn, Pascal Pigny, Jean-Pierre Aubert, Laboratoire Ecologie Fonctionnelle et Environnement (LEFE), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), and Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)
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Cancer Research ,Acylation ,[SDV]Life Sciences [q-bio] ,Molecular Sequence Data ,epithelial ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Mucin 5AC ,Biology ,Decitabine ,Hydroxamic Acids ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,0302 clinical medicine ,Epigenetics of physical exercise ,mucin ,Neoplasms ,Histone H2A ,Histone methylation ,Tumor Cells, Cultured ,Genetics ,Humans ,cancer ,Histone code ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Cancer epigenetics ,Mucin-6 ,Molecular Biology ,acetylation ,030304 developmental biology ,Epigenomics ,Mucin-2 ,0303 health sciences ,Chromosomes, Human, Pair 11 ,Mucins ,Epithelial Cells ,DNA Methylation ,Mucin-5B ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Histone Deacetylase Inhibitors ,11p15 ,030220 oncology & carcinogenesis ,Histone methyltransferase ,DNA methylation ,Azacitidine ,methylation - Abstract
International audience; The human genes MUC2, MUC5AC, MUC5B and MUC6 are clustered on chromosome 11 and encode large secreted gel-forming mucins. The frequent occurrence of their silencing in cancers and the GC-rich structure of their promoters led us to study the influence of epigenetics on their expression. Pre-and post-confluent cells were treated with demethylating agent 5-aza-2 0-deoxycytidine and histone deacetylase (HDAC) inhibitor, trichostatin A. Mapping of methylated cytosines was performed by bisulfite-treated genomic DNA sequencing. Histone modification status at the promoters was assessed by chromatin immunoprecipitation assays. Our results indicate that MUC2 was regulated by site-specific DNA methylation associated with establishment of a repressive histone code, whereas hypermethylation of MUC5B promoter was the major mechanism responsible for its silencing. DNA methyltransferase 1 was identified by small interfering RNA approach as a regulator of MUC2 and MUC5B endogenous expression that was potentiated by HDAC2. MUC2 and MUC5B epigenetic regulation was cell-specific, depended on cell differentiation status and inhibited their activation by Sp1. The expression of MUC5AC was rarely influenced by epigenetic mechanisms and methylation of MUC6 promoter was not correlated to its silencing. In conclusion, this study demonstrates the important role for methylation and/or histone modifications in regulating the 11p15 mucin genes in epithelial cancer cells.
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- 2007
3. miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer
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Nicolas Jonckheere, Audrey Vincent, Y Delpu, Belinda Duchêne, J Torrisani, Fatima Lahdaoui, Emmanuelle Leteurtre, I. Van Seuningen, Mathieu Messager, Christophe Mariette, Florence Renaud, 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, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Ecologie Fonctionnelle et Environnement (LEFE), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), and Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)
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Cancer Research ,medicine.medical_specialty ,MAP Kinase Signaling System ,[SDV]Life Sciences [q-bio] ,Pancreatic Intraepithelial Neoplasia ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Adenocarcinoma ,medicine.disease_cause ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cyclin D1 ,Internal medicine ,Pancreatic cancer ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Molecular Biology ,030304 developmental biology ,Cell Proliferation ,Regulation of gene expression ,0303 health sciences ,Mucin-4 ,Cancer ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Oncogene Protein v-akt ,MicroRNAs ,medicine.anatomical_structure ,Endocrinology ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Cancer research ,sense organs ,Pancreas ,Carcinogenesis ,Carcinoma, Pancreatic Ductal - Abstract
International audience; Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers in the world with one of the worst outcome. The oncogenic mucin MUC4 has been identified as an actor of pancreatic carcinogenesis as it is involved in many processes regulating pancreatic cancer cell biology. MUC4 is not expressed in healthy pancreas whereas it is expressed very early in pancreatic carcinogenesis. Targeting MUC4 in these early steps may thus appear as a promising strategy to slowdown pancreatic tumorigenesis. miRNA negative regulation of MUC4 could be one mechanism to efficiently downregulate MUC4 gene expression in early pancreatic neoplastic lesions. Using in silico studies, we found two putative binding sites for miR-219-1-3p in the 3 0-UTR of MUC4 and showed that miR-219-1-3p expression is downregulated both in PDAC-derived cell lines and human PDAC tissues compared with their normal counterparts. We then showed that miR-219-1-3p negatively regulates MUC4 mucin expression via its direct binding to MUC4 3 0-UTR. MiR-219-1-3p overexpression (transient and stable) in pancreatic cancer cell lines induced a decrease of cell proliferation associated with a decrease of cyclin D1 and a decrease of Akt and Erk pathway activation. MiR-219-1-3p overexpression also decreased cell migration. Furthermore, miR-219-1-3p expression was found to be conversely correlated with Muc4 expression in early pancreatic intraepithelial neoplasia lesions of Pdx1-Cre;LSL-Kras G12D mice. Most interestingly, in vivo studies showed that miR-219-1-3p injection in xenografted pancreatic tumors in mice decreased both tumor growth and MUC4 mucin expression. Altogether, these results identify miR-219-1-3p as a new negative regulator of MUC4 oncomucin that possesses tumor-suppressor activity in PDAC.
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- 2015
4. Double rôle de MUC1 dans l’ischémie-reperfusion rénale
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Brigitte Hémon, Michael Perrais, Viviane Gnemmi, Kelly Gaudelot, Sébastien Aubert, I. Van Seuningen, M. Fanchon, T. Swierczewski, and Jean-Baptiste Gibier
- Subjects
Nephrology - Abstract
Introduction Le rein a des capacites uniques de regeneration mais les mecanismes impliques sont mal compris. La plasticite des cellules epitheliales tubulaires en reponse a une agression est essentielle pour la reparation des lesions tissulaires. Cependant, a plus long terme, elle peut egalement favoriser le developpement d’une fibrose renale. MUC1 est une glycoproteine exprimee au pole apical des tubes distaux dans le rein mature. Dans le cancer, son expression est associee a la transition epithelio-mesenchymateuse (TEM) et une plus grande plasticite des cellules tumorales. Nous avons donc fait l’hypothese qu’elle pourrait aussi jouer un role dans la regeneration renale. Materiels et methodes Tout d’abord, nous avons etudie l’effet de l’hypoxie sur l’expression de MUC1 dans des cellules tubulaires humaines en culture. L’influence de MUC1 sur la resistance a l’anoikis, une forme d’apoptose, a egalement ete exploree in vitro. Puis, nous avons etabli un modele d’ischemie-reperfusion (I/R) chez des souris C57BL/6J sauvages ou invalidees pour le gene MUC1. Dans ce modele, nous avons evalue par immunohistochimie et PCR quantitative l’expression de MUC1 et de plusieurs marqueurs mesenchymateux et de pluripotence. Enfin, l’expression de ces marqueurs a ete quantifiee sur des biopsies de greffons humains precocement et a distance de la greffe. Resultats Nous avons observe une surexpression transitoire de MUC1 au niveau des cellules tubulaires en reponse a l’hypoxie et a l’ischemie. Cette induction de MUC1 etait associee a l’expression accrue de marqueurs mesenchymateux et de pluripotence ainsi qu’a une plus grande resistance a l’anoikis. Dans le modele d’I/R, MUC1 exerce une fonction nephroprotectrice durant les phases precoces. En revanche, en cas d’expression persistante lors des phases tardives, MUC1 est associee au developpement d’une fibrose plus severe. Des resultats concordants ont pu etre observes sur les biopsies de greffons. Discussion L’induction de MUC1 en reponse a une agression s’associe a une transition des cellules epitheliales tubulaires vers un phenotype mesenchymateux temoignant d’une plus grande plasticite. Cette plasticite protege initialement le rein en cas d’agression mais favorise a terme le developpement d’une fibrose. Conclusion MUC1 a un double role, protecteur puis deletere, en reponse a une agression renale.
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- 2017
5. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family
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Nicolas Skrypek, Belinda Duchêne, I. Van Seuningen, Nicolas Jonckheere, M Hebbar, Emmanuelle Leteurtre, Jonckheere, Nicolas, Inserm UMR837 Team 5, 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-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, NJ postdoctoral fellowship Ligue Nationale Contre le Cancer (LNCC), NS PhD fellowship Centre Hospitalier Régional et Universitaire (CHRU) de Lille/région Nord-Pas de Calais. Ligue Nationale Contre le Cancer (Equipe Labellisée Ligue 2010, IVS). IVS Contrat Hospitalier de Recherche Translationnelle'/CHRT 2010, AVIESAN., Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service d'oncologie médicale, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Centre de Biologie-Pathologie
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Male ,hCNT1 ,Cancer Research ,pancreatic cancer ,Equilibrative nucleoside transporter 1 ,Deoxycytidine ,NF-κB ,Small hairpin RNA ,Concentrative nucleoside transporter ,0302 clinical medicine ,Pancreatic tumor ,0303 health sciences ,biology ,gemcitabine ,Deoxycytidine kinase ,Middle Aged ,3. Good health ,Gene Expression Regulation, Neoplastic ,Biochemistry ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Multigene Family ,Female ,medicine.drug ,Antimetabolites, Antineoplastic ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Adenocarcinoma ,Models, Biological ,Article ,Equilibrative Nucleoside Transporter 1 ,03 medical and health sciences ,mucin ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Pancreatic cancer ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Molecular Biology ,030304 developmental biology ,Aged ,Mucin-4 ,Membrane Transport Proteins ,medicine.disease ,Gemcitabine ,Pancreatic Neoplasms ,Cell culture ,Drug Resistance, Neoplasm ,MUC4 ,biology.protein ,Cancer research ,sense organs - Abstract
International audience; The fluorinated analog of deoxycytidine, Gemcitabine (Gemzar), is the main chemotherapeutic drug in pancreatic cancer, but survival remains weak mainly because of the high resistance of tumors to the drug. Recent works have shown that the mucin MUC4 may confer an advantage to pancreatic tumor cells by modifying their susceptibility to drugs. However, the cellular mechanism(s) responsible for this MUC4-mediated resistance is unknown. The aim of this work was to identify the cellular mechanisms responsible for gemcitabine resistance linked to MUC4 expression. CAPAN-2 and CAPAN-1 adenocarcinomatous pancreatic cancer (PC) cell lines were used to establish stable MUC4-deficient clones (MUC4-KD) by shRNA interference. Measurement of the IC50 index using tetrazolium salt test indicated that MUC4-deficient cells were more sensitive to gemcitabine. This was correlated with increased Bax/BclXL ratio and apoptotic cell number. Expression of Equilibrative/Concentrative Nucleoside Transporter (hENT1, hCNT1/3), deoxycytidine kinase (dCK), ribonucleotide reductase (RRM1/2) and Multidrug-Resistance Protein (MRP3/4/5) was evaluated by quantitative RT-PCR (qRT-PCR) and western blotting. Alteration of MRP3, MRP4, hCNT1 and hCNT3 expression was observed in MUC4-KD cells, but only hCNT1 alteration was correlated to MUC4 expression and sensitivity to gemcitabine. Decreased activation of MAPK, JNK and NF-κB pathways was observed in MUC4-deficient cells, in which the NF-κB pathway was found to have an important role in both sensitivity to gemcitabine and hCNT1 regulation. Finally, and in accordance with our in vitro data, we found that MUC4 expression was conversely correlated to that of hCNT1 in tissues from patients with pancreatic adenocarcinoma. This work describes a new mechanism of PC cell resistance to gemcitabine, in which the MUC4 mucin negatively regulates the hCNT1 transporter expression via the NF-κB pathway. Altogether, these data point out to MUC4 and hCNT1 as potential targets to ameliorate the response of pancreatic tumors to gemcitabine treatment.
- Published
- 2013
6. The K Protein Domain That Recruits the Interleukin 1-responsive K Protein Kinase Lies Adjacent to a Cluster of c-Src and Vav SH3-binding Sites
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Karol Bomsztyk, Jerzy Ostrowski, P R Sleath, Xosé R. Bustelo, I Van Seuningen, and University of Washington [Seattle]
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Serine/threonine-specific protein kinase ,0303 health sciences ,[SDV]Life Sciences [q-bio] ,Binding protein ,Protein domain ,Cell Biology ,Biology ,Biochemistry ,SH3 domain ,MAP2K7 ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Heterogeneous-Nuclear Ribonucleoprotein K ,c-Raf ,Protein kinase A ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology - Abstract
The heterogeneous ribonucleoprotein particle (hnRNP) K protein interacts with multiple molecular partners including DNA, RNA, serine/threonine, and tyrosine kinases and the product of the proto-oncogene, Vav. The K protein is phosphorylated in vivo and in vitro on serine/threonine residues by an interleukin 1 (IL-1)-responsive kinase with which it forms a complex. In this study we set out to map the K protein domains that bind kinases. We demonstrate that the K protein contains a cluster of at least three SH3-binding sites (P1, PPGRGGRPMPPSRR, amino acids 265-278; P2, PRRGPPPPPPGRG, 285-297; and P3, RARNLPLPPPPPPRGG, 303-318) and that each one of these sites is capable of selectively engaging c-Src and Vav SH3 domains but not SH3 domains of Abl, p85 phosphatidylinositol 3-kinase, Grb-2, and Csk. We demonstrate that the K protein domain that recruits and is phosphorylated in an RNA-dependent manner by the IL-1-responsive kinase, designated KPK for K protein kinase, is contained within the 338-425-amino acid stretch and thus is contiguous but does not include the cluster of the SH3-binding sites. K protein and KPK co-immunoprecipitate from cell extracts with either c-Src or Vav, suggesting that K protein-KPK-c-Src and K protein-KPK-Vav complexes exist in vivo. Furthermore, in the context of K protein, c-Src can reactivate KPK in vitro. The succession of kinase-binding sites contained within the K protein that allow it to form multienzyme complexes and facilitate kinase cross-talk suggest that K protein may serve as a docking platform that promotes molecular interactions occurring during signal transduction.
- Published
- 1995
7. Purification, cloning, and expression of a murine phosphoprotein that binds the kappa B motif in vitro identifies it as the homolog of the human heterogeneous nuclear ribonucleoprotein K protein. Description of a novel DNA-dependent phosphorylation process
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P R Sleath, Jerzy Ostrowski, C T Rauch, B A McMullen, Karol Bomsztyk, I Van Seuningen, and Rony Seger
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Phosphoprotein ,Complementary DNA ,Heterogeneous-Nuclear Ribonucleoprotein K ,Phosphorylation ,Cell Biology ,Biology ,Molecular cloning ,Casein kinase 2 ,Heterogeneous ribonucleoprotein particle ,Molecular Biology ,Biochemistry ,Molecular biology ,Ribonucleoprotein - Abstract
The kappa B enhancer element regulates expression of many genes involved in immune responses and other processes. kappa B motif binds a number of proteins, some but not all, are related to the NF-kappa B family of transcription factors. We have previously identified a 65-kDa phosphoprotein that is specifically recognized by the kappa B motif (Ostrowski, J., Sims, J. E., Sibley, C. H., Valentine, M. A., Dower, S. K., Meier, K. E., and Bomsztyk, K. (1991) J. Biol. Chem. 266, 12722-12733). This protein is closely associated with a serine/threonine kinase that is responsive to treatment of cells with interleukin-1 and other agents. We report here purification, cloning, and expression of this kappa B motif-binding phosphoprotein. The primary structure deduced from the isolated murine cDNA, identifies the protein as the homolog of the human heterogeneous nuclear ribonucleoprotein K protein. Antipeptide antibodies and expression of the cloned cDNA in Escherichia coli, demonstrated that the K protein is the authentic phosphoprotein that binds the kappa B motif in vitro. We also demonstrate that the in vitro phosphorylation of the natural and the recombinant K proteins by the associated kinase is stimulated by the kappa B motif.
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- 1994
8. Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells
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S de Beaucé, Emmanuelle Leteurtre, Johann Merlin, I. Van Seuningen, Guillemette Huet, Laurence Stechly, Pascal Pigny, Didier Monté, VAN SEUNINGEN, ISABELLE, 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, Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] [IRI], 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, and Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé-Université de Lille, Sciences et Technologies
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Cancer Research ,medicine.medical_specialty ,Galectin 3 ,[SDV]Life Sciences [q-bio] ,Down-Regulation ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Pancreatic cancer ,Internal medicine ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Cyclin D1 ,Epidermal growth factor receptor ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Cellular localization ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,biology ,Cell growth ,Mucin-1 ,Apical membrane ,medicine.disease ,digestive system diseases ,3. Good health ,ErbB Receptors ,Pancreatic Neoplasms ,[SDV] Life Sciences [q-bio] ,Protein Transport ,Endocrinology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,RNA Interference ,Carcinogenesis ,Carcinoma, Pancreatic Ductal - Abstract
MUC1 is a transmembrane glycoprotein which is typically expressed at the apical membrane of normal epithelial cells. In cancer cells, the over-expression of MUC1 and its aberrant localization around the cell membrane and in the cytoplasm favours its interaction with different protein partners such as epidermal growth factor receptor (EGFR) and can promote tumour proliferation through the activation of oncogenic signalling pathways. Our aims were to study the mechanisms inducing MUC1 cytoplasmic localization in pancreatic cancer cells, and to decipher their impact on EGFR cellular localization and activation. Our results showed that galectin-3, an endogenous lectin, is co-expressed with MUC1 in human pancreatic ductal adenocarcinoma, and that it favours the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA interference increased the interaction between MUC1 and EGFR, EGFR and ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus. On the contrary, silencing of galectin-3 led to a decrease of cyclin-D1 levels and of cell proliferation. The galectin-3-dependent regulation of MUC1/EGFR functions may represent an interesting mechanism modulating the EGFR-stimulated cell growth of pancreatic cancer cells.
- Published
- 2011
9. Tumour growth and resistance to gemcitabine of pancreatic cancer cells are decreased by AP-2alpha overexpression
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Nicolas Jonckheere, Nathalie Saint-Laurent, I. Van Seuningen, Christiane Susini, Guillemette Huet, Nicole Porchet, Sébastien Aubert, Laurence Stechly, Pascal Pigny, Valérie Fauquette, 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, Centre de Biologie et Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), 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, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
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Cancer Research ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Blotting, Western ,pancreatic cancer ,Gene Expression ,Mice, Nude ,Biology ,medicine.disease_cause ,Transfection ,Deoxycytidine ,03 medical and health sciences ,Transactivation ,Mice ,0302 clinical medicine ,mucin ,AP-2α ,Cell Movement ,Pancreatic cancer ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,030304 developmental biology ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,0303 health sciences ,Microscopy, Confocal ,Cell growth ,gemcitabine ,Cancer ,Cell cycle ,medicine.disease ,Xenograft Model Antitumor Assays ,Pancreatic Neoplasms ,Endocrinology ,Oncology ,Transcription Factor AP-2 ,Cell culture ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,cell cycle ,Carcinogenesis ,Translational Therapeutics - Abstract
International audience; BACKGROUND: Activator protein-2alpha (AP-2alpha) is a transcription factor that belongs to the family of AP-2 proteins that have essential roles in tumorigenesis. Indeed, AP-2alpha is considered as a tumour-suppressor gene in different tissues such as colonic, prostatic or breast epithelial cells. Moreover, AP-2alpha also participates in the control of colon and breast cancer cells sensitivity towards chemotherapeutic drugs. Despite its potential interest, very few data are available regarding the roles of AP-2alpha in pancreatic cancer. METHODS: We have developed a stable pancreatic CAPAN-1 cell line overexpressing AP-2alpha. Consequences of overexpression were studied in terms of in vivo cell growth, gene expression, migration capacity and chemosensitivity. RESULTS: In vivo tumour growth of CAPAN-1 cells overexpressing AP-2alpha was significantly decreased by comparison to control cells. An altered expression pattern of cell cycle-controlling factors (CDK-4, CDK-6, cyclin-G1, p27(kip1) and p57(kip2)) was observed in AP-2alpha-overexpressing clones by microarrays and western blot analysis. Promoter activity and ChIP analysis indicated that AP-2alpha induces p27(kip1) protein levels by direct binding to and transactivation of its promoter. Moreover, AP-2alpha overexpression increased the chemosensitivity of CAPAN-1 cells to low doses of gemcitabine and reduced their in vitro migration capacity. CONCLUSION: Our data suggested that AP-2alpha overexpression could be exploited to decrease in vivo tumour growth of pancreatic cancer cells and to increase their sensitivity to gemcitabine.
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- 2009
10. Clinical impact of MUC1 and MUC4 expression in Barrett-associated oesophageal adenocarcinoma
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Christophe Mariette, J.P. Triboulet, Agnès Wacrenier, N. Briez, I. Van Seuningen, Guillaume Piessen, 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, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), VAN SEUNINGEN, ISABELLE, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
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medicine.medical_specialty ,Pathology ,Esophageal Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Adenocarcinoma ,Gastroenterology ,digestive system ,Pathology and Forensic Medicine ,Barrett Esophagus ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Metaplasia ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Biomarkers, Tumor ,medicine ,Humans ,neoplasms ,MUC1 ,030304 developmental biology ,0303 health sciences ,Mucin-4 ,business.industry ,Esophageal disease ,Mucin-1 ,Mucin ,Anatomical pathology ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,General Medicine ,Prognosis ,medicine.disease ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,Neoplasm Proteins ,3. Good health ,Dysplasia ,030220 oncology & carcinogenesis ,Disease Progression ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Immunohistochemistry ,sense organs ,medicine.symptom ,business ,Precancerous Conditions ,Follow-Up Studies - Abstract
International audience; Aims: To study the expression of MUC1 and MUC4 mucins in Barrett-associated oesophageal adenocarcinoma and coexisting lesions of the carcinogenic sequence (normal mucosa, metaplasia, dysplasia) if present, and to investigate their prognostic significance.Methods: The expression profiles of MUC1 and MUC4 were investigated by immunohistochemistry in tissue samples obtained from consecutive patients with primary surgically resected lower third oesophageal adenocarcinoma (OA) between 1997 and 2002. Histopathological parameters, recurrence and long-term survival were correlated with the number of cells stained.Results: All 52 patients exhibited OA, with 25 patients (48.1%) having associated Barrett oesophagus lesions (metaplasia or/and dysplasia). MUC1 and MUC4 were expressed in 52 and 41 of the 52 patients with adenocarcinoma (100% and 78%), respectively. All samples expressed MUC1 strongly. The prevalence of MUC4 staining was significantly decreased in metaplasia compared with normal mucosa (53% versus 92%, p
- Published
- 2009
11. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines
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I. Van Seuningen, Rutger J. Jacobs, Vânia Camilo, G. R. van den Brink, Leonor David, Rita Barros, Nuno Mendes, Bruno Pereira, Isabelle Duluc, Paula Paulo, Filipe Santos-Silva, Raquel Almeida, Jean-Noël Freund, Maria Azevedo, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), De l'homéostasie tissulaire au cancer et à l'inflammation, Institut National de la Santé et de la Recherche Médicale (INSERM), Leiden University Medical Center (LUMC), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Mucines Epitheliales : du Gene a la Fonction, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, VAN SEUNINGEN, ISABELLE, Universidade do Porto, and Gastroenterology and Hepatology
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Pathology ,medicine.medical_specialty ,Chromatin Immunoprecipitation ,animal structures ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Blotting, Western ,Bone Morphogenetic Protein 2 ,SMAD ,Bone Morphogenetic Protein 4 ,Biology ,Bone morphogenetic protein ,Pathology and Forensic Medicine ,Smad1 Protein ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Transforming Growth Factor beta ,Cell Line, Tumor ,medicine ,Humans ,CDX2 Transcription Factor ,RNA, Small Interfering ,CDX2 ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Smad4 Protein ,Regulation of gene expression ,Homeodomain Proteins ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Growth factor ,Carcinoma ,Intestinal metaplasia ,medicine.disease ,Immunohistochemistry ,BMPR1A ,digestive system diseases ,3. Good health ,[SDV] Life Sciences [q-bio] ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,embryonic structures ,Bone Morphogenetic Proteins ,Cancer research ,Ectopic expression ,RNA Interference - Abstract
Helicobacter pylori infection induces intestinal metaplasia of the stomach, a preneoplastic lesion associated with an increased risk for gastric cancer development. Intestinal metaplasia is induced by the intestine-specific transcription factor CDX2 but the mechanisms responsible for this ectopic expression have never been described. We hypothesized that the BMP/SMAD pathway has a role in CDX2 regulation, in this context, for the following reasons: (1) the BMP pathway is crucial for normal intestinal differentiation and (2) there is an influx of BMP2 and BMP4-producing cells to the stomach upon Helicobacter pylori infection. We evaluated the expression of key elements of the BMP pathway in human stomach specimens with IM. Growth factor treatments, with BMP2 and BMP4, were performed in cultured cells and a knock-down experiment of SMAD4 was done using RNAi. We showed overexpression in IM of BMP2/4, BMPR1A, and SMAD4 in 56% of IM foci, and pSMAD1/5/8 in 100% of IM foci as compared to adjacent mucosa. In vitro, treatment of AGS cells with BMP2 and BMP4 increased endogenous CDX2 expression as well as the intestinal differentiation markers MUC2 and LI-cadherin. On the other hand, SMAD4 knock-down led to decreased endogenous CDX2, MUC2, and LI-cadherin in AGS. Treatment of the SMAD4 knock-down cells had no influence on CDX2 expression as opposed to wild-type cells. A 9.3 kb CDX2 promoter could be transactivated by SMAD4 and SMAD1 in a cell-dependent manner. In conclusion, we identified for the first time that the BMP pathway is active in intestinal metaplasia and that BMP2 and BMP4 regulate CDX2 expression and promote intestinal differentiation through the canonical signal transducers.
- Published
- 2008
12. MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms
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Mahefatiana Andrianifahanana, Michael A. Hollingsworth, Jane L. Meza, Ajay P. Singh, Nicolas Moniaux, Surinder K. Batra, I. Van Seuningen, Marie-Christine Copin, J.P. Aubert, Subhash C. Chauhan, University of Nebraska [Omaha], University of Nebraska System, Mucines Epitheliales : du Gene a la Fonction, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, VAN SEUNINGEN, ISABELLE, and University of Nebraska Omaha
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,medicine.medical_specialty ,Pancreatic disease ,[SDV]Life Sciences [q-bio] ,Cystic Fibrosis Transmembrane Conductance Regulator ,Adenocarcinoma ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,Internal medicine ,Pancreatic cancer ,Genetics ,medicine ,Humans ,Gene silencing ,RNA, Messenger ,RNA, Small Interfering ,Promoter Regions, Genetic ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,DNA Primers ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Base Sequence ,Mucin-4 ,Reverse Transcriptase Polymerase Chain Reaction ,Mucins ,respiratory system ,Blotting, Northern ,medicine.disease ,digestive system diseases ,Cystic fibrosis transmembrane conductance regulator ,respiratory tract diseases ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Endocrinology ,030220 oncology & carcinogenesis ,Chloride channel ,biology.protein ,sense organs ,Pancreas ,Protein Processing, Post-Translational - Abstract
MUC4 mucin is a high molecular weight transmembrane glycoprotein that plays important roles in tumour biology. It is aberrantly expressed in pancreatic adenocarcinoma, while not being detectable in the normal pancreas. Previous studies have demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in CF, is implicated in multiple cellular functions, including gene regulation. In the present study, using a CFTR-defective pancreatic cancer cell line and its derived subline expressing functional CFTR, we report that MUC4 expression is negatively regulated by CFTR. Short-interfering RNA (siRNA)-mediated silencing of CFTR also leads to an increased expression of MUC4. Additionally, our results suggest that CFTR-mediated regulation of MUC4 is cell density-dependent and is achieved by transcriptional and posttranslational mechanisms. Moreover, in a panel of pancreatic cancer cell lines and normal pancreas, we observed that CFTR was downregulated in pancreatic cancer cells and negatively correlated with MUC4 in most cases. An aberrant expression of MUC4 was also detected in the CF pancreas. Downregulation of CFTR in pancreatic adenocarcinoma and its inverse association with the tumour-linked mucin, MUC4, indicate novel function(s) of CFTR in pancreatic tumour biology and suggest the implication of new signalling pathway(s) in MUC4 regulation.
- Published
- 2007
13. 40 The trefoil factor TFF3 promotes human airway epithelial differentiation
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Werner Hoffmann, M.-C. Coping, I. Van Seuningen, Margitta Hinz, Christelle Coraux, Marie-Pierre Buisine, Rodolphe Hajj, E. Puchelle, and Pierre Lesimple
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Pulmonary and Respiratory Medicine ,business.industry ,Human airway ,respiratory system ,medicine.disease ,Cystic fibrosis ,respiratory tract diseases ,Epithelial Differentiation ,Pediatrics, Perinatology and Child Health ,medicine ,Cancer research ,Pediatrics, Perinatology, and Child Health ,business ,Trefoil - Published
- 2006
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14. Surgery alone in the curative treatment of localised oesophageal carcinoma
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Guillaume Piessen, J.-P. Triboulet, J.M Balon, Christophe Mariette, I. Van Seuningen, Mucines Epitheliales : du Gene a la Fonction, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé
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Adult ,Male ,Poor prognosis ,medicine.medical_specialty ,Esophageal Neoplasms ,[SDV]Life Sciences [q-bio] ,030230 surgery ,Risk Assessment ,Statistics, Nonparametric ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Sex Factors ,Medicine ,Humans ,In patient ,Stage (cooking) ,Lymph node ,ComputingMilieux_MISCELLANEOUS ,Aged ,Neoplasm Staging ,Probability ,Proportional Hazards Models ,Retrospective Studies ,Therapeutic regimen ,business.industry ,Biopsy, Needle ,Age Factors ,General Medicine ,Oesophageal carcinoma ,Middle Aged ,Immunohistochemistry ,Survival Analysis ,3. Good health ,Surgery ,Esophagectomy ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,Curative treatment ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Female ,Lymph ,business ,Follow-Up Studies - Abstract
Aim To document the results of surgery alone in patients with localised oesophageal carcinoma. Methods Between January 1982 and 2002, 179 consecutive patients who underwent curative oesophagectomy for stage 0, I or II oesophageal carcinoma, without neo-adjuvant treatment, were analysed retrospectively. Results Postoperative mortality and morbidity rates were 2.8 and 30.7%, respectively. The overall actuarial survival rate at 5 years was 59%. No patients with more than four invaded lymph nodes survived 5 years. A lymph node ratio more than 0.2, more than four invaded lymph nodes and an advanced pTNM stage were predictors of poor prognosis. Conclusion Long-term survival after surgery alone for localised oesophageal carcinoma can be achieved in some 2/3rds of patients. These results should be considered before designing neo-adjuvant therapeutic regimen or embarking into exclusive treatment alternate to oesophagectomy.
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- 2004
15. Extent of oesophageal resection for adenocarcinoma of the oesophagogastric junction
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J.M Balon, I. Van Seuningen, J.-P. Triboulet, Christophe Mariette, B. Castel, Biologie et Physiopathologie des Cellules Mucipares (u377), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
- Subjects
Adult ,Male ,medicine.medical_specialty ,Esophageal Neoplasms ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Adenocarcinoma ,030230 surgery ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,medicine ,Humans ,Esophagus ,Survival rate ,Survival analysis ,ComputingMilieux_MISCELLANEOUS ,Aged ,Neoplasm Staging ,Retrospective Studies ,Aged, 80 and over ,Esophageal disease ,business.industry ,Stomach ,General Medicine ,Middle Aged ,medicine.disease ,Survival Analysis ,3. Good health ,Surgery ,Esophagectomy ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Resection margin ,Female ,Esophagogastric Junction ,business - Abstract
Aims: The optimal extent of oesophageal resection and surgical approach in patients treated for adenocarcinomas of the oesophagogastric junction (OGJ) are still uncertain. We report the correlations between resection margin involvement and outcome. Methods: Patients with positive proximal resection margin (PPRM) and those with negative proximal resection margin (NPRM) were compared. Results: Of 94 patients with macroscopically complete resection, eight were PPRM. There was no difference between the two groups in postoperative mortality or morbidity rates, in anastomotic leakage or in recurrence rates. The median survival in the PPRM group was 11.1 months compared with 36.3 months in the NPRM group ( P =0.02). No infiltration was observed in patients whose proximal margin exceeded 7 cm. The extended transthoracic approach was the only prognostic factor for tumours type II ( P =0.03, RR=1.4, 95% CI: 1.1–1.8). Conclusion: Histologic infiltration of oesophageal resection margin influences 5-year survival rate. In adenocarcinomas of the OGJ that can be treated curatively, a transection with a 8 cm oesophagectomy above the tumour in fresh specimen should be performed, and by thoracoabdominal approach for tumours type I and II.
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- 2003
16. Characterization of human mucin gene MUC4 promoter: importance of growth factors and proinflammatory cytokines for its regulation in pancreatic cancer cells
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M, Perrais, P, Pigny, M P, Ducourouble, D, Petitprez, N, Porchet, J P, Aubert, and I, Van Seuningen
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Base Sequence ,Epidermal Growth Factor ,Mucin-4 ,Transcription, Genetic ,Sp1 Transcription Factor ,Molecular Sequence Data ,Mucins ,Transforming Growth Factor alpha ,TATA Box ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Interferon-gamma ,Sp3 Transcription Factor ,Tumor Cells, Cultured ,Humans ,Cloning, Molecular ,5' Untranslated Regions ,Promoter Regions, Genetic ,Protein Kinase C ,Transcription Factors - Abstract
The human mucin gene MUC4 encodes a large transmembrane mucin that is thought to play important roles in tumor cell biology and that is overexpressed in human pancreatic carcinomas. In this report, we describe the structure and functional activity of the 5'-flanking region, including 1.0 kilobase of the promoter. The long 5'-untranslated region (2.7 kilobases) is characterized by a high content of GC in its 3'-end. The first TATA box was located at -2672/-2668. Multiple transcription start sites and a high density of putative binding sites for Sp1 (GC and CACCC boxes), AP-1/-2/-4, cAMP-responsive element-binding protein, GATA, GR, and STAT transcription factors were found within the 5'-flanking region. Transcriptional activity of the promoter was assessed using pGL3-luciferase deletion mutants in two MUC4-expressing (CAPAN-1 and CAPAN-2) and one nonexpressing (PANC-1) pancreatic cancer cell line. Two highly active fragments (-219/-1 and -2781/-2572) that drive MUC4 transcription in CAPAN-1 and CAPAN-2 cells were identified. Gel retardation assays indicated that Sp1 and Sp3 bind to cognate cis-elements found in the 5'-flanking region and that Sp1 transactivates, whereas Sp3 inhibits the GC-rich region (-464/-1) in CAPAN-2 cells. Activation of protein kinase C with phorbol ester and treatment of cells with epidermal growth factor and transforming growth factor-alpha resulted in up-regulation of the promoter. Tumor necrosis factor-alpha and interferon (IFN)-gamma inflammatory cytokines had no or mild effect on MUC4 transcriptional activity when used alone. However, a very strong synergistic effect (10-12-fold activation) between IFN-gamma and tumor necrosis factor-alpha or IFN-gamma and transforming growth factor-alpha was obtained in CAPAN-2 cells. Altogether these results demonstrate that the 5'-flanking region of MUC4 contains epithelial cell-specific, positive, and negative regulatory cis-elements, that Sp1/Sp3 are important regulators of MUC4 basal expression, and that its regulation in pancreatic cancer cells involves complex interplay between several signaling pathways.
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- 2001
17. Aberrant expression of human mucin gene MUC5B in gastric carcinoma and cancer cells. Identification and regulation of a distal promoter
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M, Perrais, P, Pigny, M P, Buisine, N, Porchet, J P, Aubert, and I, Van Seuningen-Lempire
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Base Sequence ,Transcription, Genetic ,Molecular Sequence Data ,Mucins ,DNA ,Adenocarcinoma ,Mucin-5B ,TATA Box ,Gene Expression Regulation, Neoplastic ,Stomach Neoplasms ,Tumor Cells, Cultured ,Humans ,RNA, Messenger ,Promoter Regions, Genetic ,Signal Transduction - Abstract
In gastric cancer, altered expression of MUC1, MUC2, MUC5AC, and MUC6 mucin genes has already been described. We show in this report by the means of in situ hybridization, reverse transcriptase-polymerase chain reaction, and transfection assays that MUC5B is also abnormally expressed in gastric carcinomatous tissues and cell lines. We thus undertook to elucidate the molecular mechanisms that regulate the transcription of MUC5B in gastric cancer cells. To this end, high expressing (KATO-III) and low expressing (AGS) gastric cancer cell lines were chosen to study human mucin gene MUC5B expression and promoter activity. Sequencing of the promoter region revealed a distal TATA box located 1 kilobase upstream of the proximal TATA box. Functional activity of the promoter was addressed by using deletion mutants covering 2044 nucleotides upstream of the MUC5B transcription start site. We identified a distal promoter 10 times more active than the proximal promoter in KATO-III cells. In AGS cells, both promoters, much less active, showed the same range of activity. Binding assays allowed us to show that the transcription factor ATF-1 binds to a cis-element present in the distal promoter. Sp1, which binds to both promoters specifically transactivates the proximal promoter. Treatment of transfected cells with PMA, cholera toxin A subunit, and calcium ionophore showed that only PMA led to a substantial activation of the distal promoter. MUC5B 5'-flanking region having a high GC content, influence of methylation on the MUC5B expression was assessed. Our results indicate that repression of MUC5B expression visualized in AGS cells is due in part to the presence of numerous methylated cytosine residues throughout the 5'-flanking region. Altogether these results demonstrate that MUC5B expression in gastric cancer cells is governed by a highly active distal promoter that is up-regulated by protein kinase C and that repression is under the influence of methylation.
- Published
- 2001
18. P003 Selective inhibition of eIF2alpha dephosphorylation prevents colitis and shows therapeutic potential in a new model of ulcerative colitis
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Yoram Bouhnik, Melissa Vallee, Jean-Noël Freund, Frédérick Barreau, Eric Ogier-Denis, Eric Pedruzzi, Dominique Cazals-Hatem, Shirin Sedghi, Fanny Daniel, Nicolas Montcuquet, Jean-Pierre Hugot, Xavier Treton, I. Van Seuningen, Yannick Ladeiro, and Cécile Guichard
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Dephosphorylation ,business.industry ,Gastroenterology ,medicine ,Cancer research ,General Medicine ,Colitis ,Selective inhibition ,medicine.disease ,business ,Ulcerative colitis - Published
- 2013
19. Caractérisation des lésions prénéoplasiques coliques : intérêt des gènes de mucines MUC5AC et MUC2
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Florence Renaud, Audrey Vincent, Christophe Mariette, Stéphanie Truant, David Buob, I. Van Seuningen, Marie-Christine Copin, Emmanuelle Leteurtre, and Marie-Pierre Buisine
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Pathology and Forensic Medicine - Published
- 2012
20. The K protein domain that recruits the interleukin 1-responsive K protein kinase lies adjacent to a cluster of c-Src and Vav SH3-binding sites. Implications that K protein acts as a docking platform
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I, Van Seuningen, J, Ostrowski, X R, Bustelo, P R, Sleath, and K, Bomsztyk
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Binding Sites ,Recombinant Fusion Proteins ,Molecular Sequence Data ,Cell Cycle Proteins ,In Vitro Techniques ,Peptide Mapping ,Heterogeneous-Nuclear Ribonucleoproteins ,Enzyme Activation ,Heterogeneous-Nuclear Ribonucleoprotein K ,src Homology Domains ,Mice ,Ribonucleoproteins ,Proto-Oncogene Proteins ,Animals ,Amino Acid Sequence ,Proto-Oncogene Proteins c-vav ,Protein Kinases ,Interleukin-1 ,Protein Binding - Abstract
The heterogeneous ribonucleoprotein particle (hnRNP) K protein interacts with multiple molecular partners including DNA, RNA, serine/threonine, and tyrosine kinases and the product of the proto-oncogene, Vav. The K protein is phosphorylated in vivo and in vitro on serine/threonine residues by an interleukin 1 (IL-1)-responsive kinase with which it forms a complex. In this study we set out to map the K protein domains that bind kinases. We demonstrate that the K protein contains a cluster of at least three SH3-binding sites (P1, PPGRGGRPMPPSRR, amino acids 265-278; P2, PRRGPPPPPPGRG, 285-297; and P3, RARNLPLPPPPPPRGG, 303-318) and that each one of these sites is capable of selectively engaging c-Src and Vav SH3 domains but not SH3 domains of Abl, p85 phosphatidylinositol 3-kinase, Grb-2, and Csk. We demonstrate that the K protein domain that recruits and is phosphorylated in an RNA-dependent manner by the IL-1-responsive kinase, designated KPK for K protein kinase, is contained within the 338-425-amino acid stretch and thus is contiguous but does not include the cluster of the SH3-binding sites. K protein and KPK co-immunoprecipitate from cell extracts with either c-Src or Vav, suggesting that K protein-KPK-c-Src and K protein-KPK-Vav complexes exist in vivo. Furthermore, in the context of K protein, c-Src can reactivate KPK in vitro. The succession of kinase-binding sites contained within the K protein that allow it to form multienzyme complexes and facilitate kinase cross-talk suggest that K protein may serve as a docking platform that promotes molecular interactions occurring during signal transduction.
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- 1995
21. 190 The Mucin MUC4-mediated Chemoresistance of Human Pancreatic Cancer Cells to Gemcitabine and FOLFIRINOX
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Mohamed Hebbar, N. Jonchkeere, Belinda Duchêne, I. Van Seuningen, Emmanuelle Leteurtre, and Nicolas Skrypek
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,FOLFIRINOX ,Mucin ,medicine.disease ,Gemcitabine ,Pancreatic cancer ,Internal medicine ,medicine ,business ,medicine.drug - Published
- 2012
22. 344 The MUC1 Membrane-bound Mucin is an Actor in Renal Clear-cell Carcinoma
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Bélinda Ringot, Laurent Zini, Audrey Bouillez, A. Aubert, Michael Perrais, Caroline Butruille, Xavier Leroy, Viviane Gnemmi, and I. Van Seuningen
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Oncology ,Renal clear cell carcinoma ,Cancer Research ,medicine.medical_specialty ,Membrane bound ,Chemistry ,Internal medicine ,Mucin ,Cancer research ,medicine ,MUC1 - Published
- 2012
23. MUC1 is a target of hypoxia-inducible factor transcription factor in renal clear carcinomatous cells
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Brigitte Hémon, Michael Perrais, Sébastien Aubert, Nicole Porchet, Xavier Leroy, and I. Van Seuningen
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Cancer Research ,Oncology ,Hypoxia-inducible factors ,Serum response factor ,Cancer research ,Biology ,Transcription factor ,MUC1 - Published
- 2008
24. 082 Le peptide trifolié TFF3 favorise la différenciation ciliée de l’épithélium respiratoire de surface humain
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E. Puchelle, Marie-Christine Copin, Marie-Pierre Buisine, Christelle Coraux, I. Van Seuningen, Werner Hoffmann, Margitta Hinz, Sl. Brody, Pierre Lesimple, and Rodolphe Hajj
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Pulmonary and Respiratory Medicine - Published
- 2006
25. Rôles des interactions e-cadhérine - e-cadhérine sur l’inhibition de la croissance cellulaire. implications des e-caténines et de la voie PI3K
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I. Van Seuningen, B.M. Gumbiner, and Michael Perrais
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business.industry ,Gastroenterology ,Medicine ,General Medicine ,business ,Molecular biology - Published
- 2006
26. Régulation épigénétique des genes de mucines 11p15 (MUC2, MUC5AC, MUC5B, MUC6) dans des lignées épithéliales cancéreuses et dans les tissus de malades
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I. Van Seuningen, Pascal Pigny, Jean-Luc Desseyn, and Audrey Vincent
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business.industry ,Gastroenterology ,Medicine ,General Medicine ,business ,Molecular biology - Published
- 2006
27. Spontaneous development of colitis in mice deficient for Mucin 2
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I van Seuningen, M van der Sluis, Jan P. Dekker, A. W.C. Einerhand, Ingrid B. Renes, HA B ller, Bae de Koning, and Anna Velcich
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Hepatology ,business.industry ,Immunology ,Gastroenterology ,medicine ,Mucin 2 ,Colitis ,medicine.disease ,business - Published
- 2006
28. C30 - Régulation de l’expression du gène de mucine MUC1 par les acides biliaires dans des modèles cellulaires et tissulaires humains d’adénocarcinome de l’œsophage
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J.P. Triboulet, Christophe Mariette, Brigitte Hémon, Guillaume Piessen, I. Van Seuningen, Emmanuelle Leteurtre, and J.P. Aubert
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business.industry ,Gastroenterology ,Medicine ,General Medicine ,business ,Molecular biology - Published
- 2006
29. Important role for Mucin 2 in colonic protection against dextran sulfate sodium
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J.B. van Goudoever, M van der Sluis, Jan P. Dekker, A. W.C. Einerhand, Ingrid B. Renes, Anna Velcich, I van Seuningen, and HA B ller
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Hepatology ,Biochemistry ,business.industry ,Gastroenterology ,Medicine ,Mucin 2 ,business ,Dextran Sulfate Sodium - Published
- 2006
30. C31 - Régulation épigénétique des gènes de mucines 11P15 (MUC6, MUC2, MUC5AC et MUC5B) dans des lignées cancéreuses de différentes origines épithéliales
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Christophe Mariette, Audrey Vincent, I. Van Seuningen, and Marie-Paule Ducourouble
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business.industry ,Gastroenterology ,Medicine ,General Medicine ,business ,Molecular biology - Published
- 2006
31. Regulation of murine Muc5ac mucin gene expression by GATA-6 and HNF-4?? transcription factors during stomach development
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Marie-Paule Ducourouble, A. W.C. Einerhand, Ingrid B. Renes, I van Seuningen, A M Korteland-Van Male, and N Jonckheere
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Regulation of gene expression ,Hepatology ,business.industry ,GATA2 ,Response element ,Gastroenterology ,Promoter ,E-box ,TCF4 ,Cell biology ,Sp3 transcription factor ,Medicine ,business ,STAT6 - Published
- 2006
32. 014 Expression différentielle des mucines et des peptides trifoliés (TFF) durant la régénération de l’épithélium respiratoire humain
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I. Van Seuningen, Christelle Coraux, E. Puchelle, Marie-Pierre Buisine, C. Catusse, Marie-Christine Copin, Nicole Porchet, and Pierre Lesimple
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Pulmonary and Respiratory Medicine - Abstract
Introduction L’epithelium respiratoire est frequemment endommage par divers facteurs inhales qui provoquent la rupture de la barriere epitheliale et une desquamation. Il doit donc regenerer pour pouvoir assurer sa fonction de protection. Les mecanismes a l’origine de la regeneration d’un epithelium humain differencie sont mal connus. La famille des TFF comprend 3 membres (TFF1 a 3) secretes par les epitheliums muqueux. Avec les mucines, ils sont les composants majeurs des mucus biologiques. Les mucines sont des glycoproteines de haut poids moleculaire, secretees (MUC2, 5AC, 5B et 6) ou membranaires (MUC 1, 3 et 4). Les roles des TFF et des mucines dans la regeneration et la differenciation de l’epithelium respiratoire ne sont pas connus. Materiel et methodes Pour etudier les mecanismes de regeneration et de differenciation de l’epithelium respiratoire humain, nous avons utilise un modele de culture en interface air-liquide et un modele de xenogreffe bronchique dans la souris NUDE. Tous deux miment la regeneration de l’epithelium humain normal: migration, proliferation, et enfin differenciation des cellules epitheliales humaines. Nous avons examine l’expression des mucines (MUC1, 4, 5AC et 5B) et des TFF au cours de ces etapes, par RT-PCR et/ou immu-nohistochimie. Resultats Les ARNm de MUC1 et 4 sont detectes tres tot et leur expression est maintenue tout au long de la regeneration. A l’inverse, MUC5AC, 5B et TFF3 ne sont transcrits que dans l’epithelium differencie. MUC1 est identifiee au niveau de la membrane apicale des cellules, alors que MUC4 est detectee dans le cytoplasme des cellules migratoires et malpighiennes. Dans l’epithelium differencie, MUC4 est presente dans le cytoplasme de toutes les cellules. MUC5AC est detectable dans les granules secretoires des cellules a mucus. MUC5B et TFF3 n’apparaissent que dans les granules secretoires des cellules caliciformes bien differenciees. Alors que toutes les cellules caliciformes expriment MUC5AC, certaines ne sont pas marquees par les anticorps MUC5B ou TFF3, suggerant l’existence de sous-types de cellules caliciformes. Conclusion Ces resultats demontrent que les TFF et les mucines ont des profils d’expression differents au cours de la regeneration de l’epithelium respiratoire humain, suggerant des roles distincts dans la protection et la differenciation de la muqueuse respiratoire.
- Published
- 2005
33. P0608 DISTINCT EXPRESSION OF THE MEMBRANE-BOUND MUCINS MUC3 AND MUC4 IN EXPERIMENTAL COLITIS
- Author
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Marie-Paule Ducourouble, A. M. Korteland-Van Male, M van der Sluis, A. W.C. Einerhand, I van Seuningen, H. A. B ller, and M. H. M. Melis
- Subjects
Membrane bound ,business.industry ,Pediatrics, Perinatology and Child Health ,Mucin ,Gastroenterology ,Experimental colitis ,Medicine ,business ,Cell biology - Published
- 2004
34. Helicobacter pylori urease and flagellin alter mucin gene expression in human gastric cancer cells
- Author
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Marie-Paule Ducourouble, Michael Perrais, Christel Rousseaux, Nicolas Jonckheere, René J. Courcol, Pascal Vincent, Isabelle Van Seuningen, VAN SEUNINGEN, ISABELLE, 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, Institut de biologie de Lille - UMS 3702 (IBL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), This work was supported by the European Regional Development Fund (I. Van Seuningen). This work received the Janssen-Cylen Award at the GEFH (Groupe d’Etude Français des Helicobacter) Helicobacter pylori Day, Institut Pasteur, Paris, France., We thank Danièle Petitprez for her excellent technical help and Dr. Agnès Labigne for the gift of the Helicobacter pylori mutated strains (Institut Pasteur, Pathogénie bactérienne des muqueuses, Paris)., Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille
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Cancer Research ,Mucin 5AC ,0302 clinical medicine ,Gene expression ,Tumor Cells, Cultured ,Medicine ,Regulation of gene expression ,0303 health sciences ,biology ,Virulence ,Reverse Transcriptase Polymerase Chain Reaction ,Stomach ,Gastroenterology ,NF-kappa B ,General Medicine ,respiratory system ,Urease ,3. Good health ,Gene Expression Regulation, Neoplastic ,Oncology ,Cytokines ,030211 gastroenterology & hepatology ,Blotting, Western ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Real-Time Polymerase Chain Reaction ,digestive system ,Microbiology ,Helicobacter Infections ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Stomach Neoplasms ,CagA ,Humans ,RNA, Messenger ,Gene ,030304 developmental biology ,Helicobacter pylori ,business.industry ,Mucin ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,biology.organism_classification ,MUC5AC ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,digestive system diseases ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,biology.protein ,[SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,business ,Flagellin - Abstract
International audience; Background Helicobacter pylori (Hp), which is one of the causative agents in human gastric adenocarcinoma, is known to interact with mucous gel and alter mucin gene expression. The aim of this work was to study, using an in vitro model of cell infection, the effects of urease, flagellin, and CagA vir-ulence factors on the regulation of the four 11p15 mucin genes (MUC2, MUC5AC, MUC5B, and MUC6). Methods KATO-III and AGS gastric cancer cells were infected for 1, 3 or 6 h with Hp wild-type strains (ATCC 43504, N6, and SS1) or corresponding isogenic mutants deficient for urease subunit B, flagellin subunit A, and CagA. mRNA levels of MUC2, MUC5B, MUC5AC and MUC6 were assessed by RT-PCR, and functional activity of their promoters was measured by transient transfection assays. Results Infection of KATO-III cells with Hp wild-type strains resulted in an early (at 1 h) transient expression of MUC2, MUC5AC, and MUC6 mRNA concomitant with those of interleukin (IL)-1b, IL-8, and TNF-a cytokines. In these cells, the UreB-isogenic mutant induced strong activation of MUC5AC expression, and UreB-responsive elements were located in the-486/-1 region of the promoter. FlaA-and CagA-mutants had no effect on mucin gene mRNA levels in KATO-III cells. In AGS cells, Hp-responsive elements were identified in all promoters, and overexpression of NF-jB induced upregulation of MUC5AC promoter activity when infected with the UreB-isogenic mutant. Conclusion These results indicate that Hp infection of gastric cancer cells alters 11p15 mucin gene transcription and that MUC5AC downregulation is mediated by urease virulence factor.
- Published
- 2013
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