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1. Immune-Mediated Necrotizing Myopathy (IMNM): A Story of Antibodies

Author

Sarah Julien, Inès Challier, Marine Malleter, Fabienne Jouen, Laurent Drouot, and Olivier Boyer

Subjects
immune-mediated necrotizing myopathy, myositis, anti-SRP, anti-HMGCR, autoantibodies, Immunologic diseases. Allergy, RC581-607
Abstract

Immune-mediated necrotizing myopathy (IMNM) is a rare and severe disease that corresponds to a specific entity of idiopathic inflammatory myopathy. Patients with IMNM suffer from proximal muscle weakness, and present high levels of creatine kinase and necrotic myofibers. Anti-Signal Recognition Particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies (HMGCR) have recently been identified in two thirds of patients with IMNM and are used as a hallmark of the disease. In this review, we provide a detailed description of these antibodies and the tests used to detect them in the serum of patients. Based on in vitro studies and mouse models of IMNM, we discuss the role of autoantibodies in the pathogenesis of the disease. Finally, in the light of the latest knowledge, we conclude with a review of recent therapeutic approaches in IMNM.

Published
2024
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3. Supplementary Figures 1 - 5 from CD95L Cell Surface Cleavage Triggers a Prometastatic Signaling Pathway in Triple-Negative Breast Cancer

Author

Patrick Legembre, Pierre Vacher, Yves Collette, Laure Debure, Gaëtan MacGrogan, Thomas Ducret, Mario Campone, Loic Campion, Pascal Jézéquel, Jean Levêque, Florence Godey, Armelle Goubard, Rémy Castellano, Alban Bessede, Sébastien Tauzin, and Marine Malleter

Abstract

PDF file - 3848K, Figure S1. Pathological doses of cl-CD95L trigger cell migration of TNBC cells. Figure S2. Cl-CD95L induces migration of TNBC cells through a PI3K(p110β)/c-yesdriven signaling pathway. Figure S3. NOX-3-dependent ROS production is instrumental in CD95-mediated cell motility in TNBC cells. Figure S4. Cl-CD95L induces co-localization of CD95 with EGFR. Figure S5. cl-CD95L promotes migration of TNBC cells via EGFR-dependent and EGFindependent signaling pathways.

Published
2023
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5. Correction to A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

Author

Hariniaina Rampanarivo, Mickael Jean, Amélie Fouqué, Patrick Legembre, Mac Dinh Hung, Kenji F. Shoji, Yves Collette, Marine Malleter, Rémy Castellano, Emmanuelle Josselin, Pierre van de Weghe, Olivier Delalande, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structures et interactions moléculaires, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interactions cellulaires et moléculaires (ICM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), and Bidaut, Ghislain

Subjects
Antitumor activity, Chemistry, In vivo, Covalent bond, Drug Discovery, Cancer research, Molecular Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Discovery and development of mTOR inhibitors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Triple-negative breast cancer, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract

International audience

Published
2019
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6. Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility

Author

Florent Dufour, Marine Malleter, Amélie Fouqué, Thierry Levade, Guillaume Poiroux, Aude Dupuy, Aubin Penna, Patrick Legembre, Kenji F. Shoji, Sébastien Tauzin, Valérie Edmond, Nathalie Théret, Olivier Micheau, Bruno Ségui, Ruth Rimokh, Odile Sergent, Jonchère, Laurent, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), INSERM UMR 1037, CNRS ERL 505294, CRCT ( UPS ), UNIVERSITE TOULOUSE, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Hôpital de Rangueil-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Cancer Research, Ceramide, Epithelial-Mesenchymal Transition, Membrane Fluidity, [SDV]Life Sciences [q-bio], Cell, Down-Regulation, Motility, HL-60 Cells, Biology, Jurkat Cells, chemistry.chemical_compound, Cell Movement, Neoplasms, Sphingosine N-Acyltransferase, Genetics, medicine, Membrane fluidity, Humans, Epithelial–mesenchymal transition, Molecular Biology, Ceramide synthase, Cells, Cultured, [ SDV ] Life Sciences [q-bio], Cell Membrane, Membrane Proteins, Cell migration, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, chemistry, Cancer cell, K562 Cells
Abstract

International audience; Epithelial-to-mesenchymal transition (EMT) promotes cell motility, which is important for the metastasis of malignant cells, and blocks CD95-mediated apoptotic signaling triggered by immune cells and chemotherapeutic regimens. CD95L, the cognate ligand of CD95, can be cleaved by metalloproteases and released as a soluble molecule (cl-CD95L). Unlike transmembrane CD95L, cl-CD95L does not induce apoptosis but triggers cell motility. Electron paramagnetic resonance was used to show that EMT and cl-CD95L treatment both led to augmentation of plasma membrane fluidity that was instrumental in inducing cell migration. Compaction of the plasma membrane is modulated, among other factors, by the ratio of certain lipids such as sphingolipids in the membrane. An integrative analysis of gene expression in NCI tumor cell lines revealed that expression of ceramide synthase-6 (CerS6) decreased during EMT. Furthermore, pharmacological and genetic approaches established that modulation of CerS6 expression/activity in cancer cells altered the level of C16-ceramide, which in turn influenced plasma membrane fluidity and cell motility. Therefore, this study identifies CerS6 as a novel EMT-regulated gene that has a pivotal role in the regulation of cell migration.Oncogene advance online publication, 17 March 2014; doi:10.1038/onc.2014.55.

Published
2014
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7. CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice

Author

Patrick Blanco, Patrick Legembre, Paul A. Barrow, Aubin Penna, Cécile Contin-Bordes, Marine Malleter, Robin J. Flynn, Jerome Ritz, Thomas Ducret, Roselyne Viel, Florence Poizeau, Julien Seneschal, Alain Dupuy, Nathalie Rioux, Lucie Morere, Florence Jouan, Pierre Vacher, Matthieu Le Gallo, Alain Fautrel, Amanda Poissonnier, Edouard Forcade, Doriane Sanséau, Anne-Marie Vacher, Nicolas Levoin, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Bioprojet, H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2, INCa PLBIO, Ligue Contre le Cancer, INSERM Transfert, Fondation ARC, Region Bretagne, Rennes Metropole, University of Nottingham Faculty of Medicine, Biotechnology and Biological Sciences Research Council [BB/M018369/1], ANR [ANR-12-JSV2-0004-001], ANR-12-JSV2-0004,Ca-DoS,Vivre ou Mourir : Le calcium comme point de contrôle déterminant le destin d'une cellule suite à la stimulation des récepteurs de mort.(2012), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Mice, Inbred MRL lpr, Lymphocyte, receptor, cd95, ligand, T-Lymphocytes, Regulatory, chemistry.chemical_compound, Mice, Sphingosine, Immunology and Allergy, Lupus Erythematosus, Systemic, Interferon gamma, Cells, Cultured, Th17 cell, Systemic lupus erythematosus, Interleukin-17, apoptosis, Fas receptor, autoimmune lymphoproliferative syndrome, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, sh3 domain, Female, Interleukin 17, Signal transduction, medicine.drug, Immunology, fas gene-mutations, Biology, 03 medical and health sciences, Interferon-gamma, Immune system, sphingosine-1 phosphate, death, medicine, Animals, Humans, Protein Interaction Domains and Motifs, Sphingosine-1-phosphate, Calcium Signaling, fas Receptor, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Phospholipase C gamma, pathway, Transendothelial and Transepithelial Migration, lupus, medicine.disease, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, chemistry, inflammation, Th17 Cells, Calcium, Lysophospholipids, Transcriptome, protein
Abstract

International audience; CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.

Published
2016
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8. The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria

Author

Pierre Vacher, Marine Malleter, Yves Gouriou, Chi Li, L. Debure, Patrick Legembre, E. Lepvrier, Vanessa Delcroix, Amélie Fouqué, Mehdi Hammadi, Michel Ovize, Thomas Ducret, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-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)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié - CRLCC Bordeaux, Hospices Civils de Lyon, Departement de Neurologie (HCL), CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), ARC, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, CA106599, NIH, National Institutes of Health, CA175003, NIH, National Institutes of Health, GM106386, NIH, National Institutes of Health, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut Bergonié [Bordeaux], UNICANCER, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and TAN, Yossan-Var

Subjects
0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], bcl-X Protein, Down-Regulation, Apoptosis, Triple Negative Breast Neoplasms, Mitochondrion, Biology, Endoplasmic Reticulum, Models, Biological, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Animals, Humans, Calcium Signaling, fas Receptor, Molecular Biology, PI3K/AKT/mTOR pathway, Calcium signaling, Mice, Knockout, Original Paper, Cell growth, Endoplasmic reticulum, Voltage-Dependent Anion Channel 1, Cell migration, Cell Biology, 3. Good health, Cell biology, Mitochondria, [SDV] Life Sciences [q-bio], 030104 developmental biology, 030220 oncology & carcinogenesis, Mitochondrial Membranes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Calcium, Female, bcl-Associated Death Protein, Calcium Channels, Signal transduction, BH3 Interacting Domain Death Agonist Protein, Protein Binding
Abstract

International audience; Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca 2+ signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca 2+ transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca 2+ uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs.

Published
2016
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9. Study of Antiproliferative Effects of Synthetic Substances Against Lens Epithelial Cell Line (SRA 01/04)

Author

Bénédicte Rousseau, Catherine Jacquot, Marine Malleter, Christophe Tomasoni, Didier Ducourneau, Philippe Tourette, Alain Pineau, and Christos Roussakis

Subjects
medicine.medical_specialty, genetic structures, Biology, Cataract, Cell Line, Flow cytometry, Cataracts, Lens, Crystalline, medicine, Humans, Pharmacology (medical), IC50, Cell Proliferation, Pharmacology, medicine.diagnostic_test, Cell growth, Cell Cycle, Epithelial Cells, Lens epithelial cell, medicine.disease, eye diseases, In vitro, Surgery, Ophthalmology, medicine.anatomical_structure, Pharmaceutical Preparations, Cell culture, Lens (anatomy), Cancer research, sense organs
Abstract

A cataract is a clouded area of the eye, which impairs vision. Cataracts can be caused by a natural hardening of the lens in the elderly, or may be the result of eye injury. However there is a treatment by extracapsular surgery, almost 50% of operations are followed by another posterior capsule opacification. This secondary cataract is due to abnormal cellular proliferation. Pharmacologic inhibition of this cellular proliferation would be a very promising treatment. The objective of our study is to test some antiproliferative drugs, less toxic than those currently used such as 5-FU or mytomycin C. We have investigated the in vitro effects of several molecules (V0 and its derivatives) on a proliferative human lens epithelial cell line (SRA 01/04). During a first step, we have measured the IC50 of each molecule. After this first screening, we have studied the kinetic of the cell growth with or without the molecules at different concentration. Then, flow cytometry was used to determine the phase of the cell cycle at which the proliferation stopped. This study has shown that 3 molecules V19, V1, and A190 have an interesting profile in vitro and were selected to analyze their mechanism of action.

Published
2012
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10. Antiproliferative activity against human non-small cell lung cancer of two O-alkyl-diglycosylglycerols from the marine sponges Myrmekioderma dendyi and Trikentrion laeve

Author

Audrey Robic, Marine Malleter, Jean-Michel Kornprobst, Christos Roussakis, Fereshteh Farokhi, Gilles Barnathan, Cécile Debitus, Gaëtane Wielgosz-Collin, Institut Des Substances et Organismes de la Mer - UR 2160 (ISOMER), Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ), Adaptation aux milieux extrêmes, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), and Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)

Subjects
Lung Neoplasms, Stereochemistry, Antineoplastic Agents, Xylose, chemistry.chemical_compound, Glycolipid, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Discovery, medicine, Glycerol, Animals, Humans, [CHIM]Chemical Sciences, Lung cancer, Alkyl, Cell Proliferation, Pharmacology, chemistry.chemical_classification, biology, Organic Chemistry, Biological activity, Alkyldiglycosylglycerols Glycolipids Human lung cancer Marine sponges Myrmekioderma Trikentrion, General Medicine, medicine.disease, biology.organism_classification, Porifera, Sponge, chemistry, Biochemistry, Cell culture, lipids (amino acids, peptides, and proteins), Glycolipids
Abstract

International audience; Glycolipids of Myrmekioderma sponges contain Myrmekiosides, a new family of glycolipids with a unique structure of mono-O-alkyl-diglycosylglycerols. This report deals with the identification and biological activity of the new Myrmekioside E from Myrmekioderma dendyi. Its structure has been elucidated from spectroscopic data and chemical degradation studies. It contained a glycerol backbone linked to xylose and N-acetylglucosamine, and an alkyl long-chain with a terminal alcohol group. A related glycolipid, Trikentroside, known in the sponge Trikentrion laeve, was subjected to a comparative biological evaluation. Both glycolipids inhibit proliferation of two human non-small cell lung cancer cell lines (NSCLC-N6 and A549).

Published
2012
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11. A Novel Covalent mTOR Inhibitor, DHM25, Shows in Vivo Antitumor Activity against Triple-Negative Breast Cancer Cells

Author

Yves Collette, Kenji F. Shoji, Olivier Delalande, Rémy Castellano, Mac Dinh Hung, Patrick Legembre, Marine Malleter, Mickael Jean, Emmanuelle Josselin, Pierre van de Weghe, Hariniaina Rampanarivo, Amélie Fouqué, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut des Sciences Chimiques de Rennes (ISCR), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Oncogenesis Stress Signaling (OSS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Institut National Du Cancer, Ministère de l'Enseignement Supérieur et de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Comité du Morbihan, Ligue Nationale Contre le Cancer, Comité de Maine-et-Loire, Ligue Nationale Contre le Cancer, Comité des Côtes-d'Armor, Ligue Nationale Contre le Cancer, Comité du Finistère, Ligue Nationale Contre le Cancer, Comité d’Ille-et-Vilaine, Ligue Nationale Contre le Cancer, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR), and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)

Subjects
Models, Molecular, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Breast Neoplasms, Metastasis, Mice, Structure-Activity Relationship, Mice, Inbred NOD, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Kinome, Benzopyrans, Kinase activity, Phosphorylation, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, Phosphoinositide-3 Kinase Inhibitors, Kinase, Chemistry, TOR Serine-Threonine Kinases, RPTOR, medicine.disease, Molecular biology, 3. Good health, Oncogene Protein v-akt, Cancer cell, Cancer research, Molecular Medicine, Female, Drug Screening Assays, Antitumor, Signal Transduction
Abstract

International audience; Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology

Published
2015
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12. TP53 transcription factor for the NEDD9/HEF1/Cas-L gene: potential targets in Non-Small Cell Lung Cancer treatment

Author

Bénédicte Rousseau, Catherine Jacquot, Christos Roussakis, Marine Malleter, Tifenn Boutard, Vehary Sakanyan, Christophe Tomasoni, Julie Le Palabe, Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
Chromatin Immunoprecipitation, Lung Neoplasms, NEDD9 Gene, [SDV]Life Sciences [q-bio], Mutant, Apoptosis, Nerve Tissue Proteins, Biology, Real-Time Polymerase Chain Reaction, NEDD9, medicine.disease_cause, Article, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, medicine, Humans, Lung cancer, Transcription factor, Adaptor Proteins, Signal Transducing, Mutation, Multidisciplinary, Triazines, Cell growth, Membrane Proteins, Oncogenes, Phosphoproteins, medicine.disease, G1 Phase Cell Cycle Checkpoints, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Cell culture, Tumor Suppressor Protein p53, Non-small-cell lung cancer
Abstract

Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells and the high rate of mutation of the TP53 gene in all cancers and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells.

Published
2015
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13. Cucurbitacin-D-induced CDK1 mRNA up-regulation causes proliferation arrest of a non-small cell lung carcinoma cell line (NSCLC-N6)

Author

Catherine, Jacquot, Benedicte, Rousseau, Delphine, Carbonnelle, Ioanna, Chinou, Marine, Malleter, Christophe, Tomasoni, and Christos, Roussakis

Subjects
Gene Expression Regulation, Neoplastic, Lung Neoplasms, Dose-Response Relationship, Drug, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, CDC2 Protein Kinase, Humans, Cell Cycle Checkpoints, RNA, Messenger, Antineoplastic Agents, Phytogenic, Triterpenes, Cell Proliferation, Up-Regulation
Abstract

Despite progress in chemotherapeutic agents, non-small cell lung cancers (NSCLC) still have a poor survival rate. Thus, development of new therapeutic strategies, specifically against cancer cells is still required. For this purpose, we treated the non-small cell lung cancer cell line NSCLC-N6 with the natural product cucurbitacin D (CucD) - extracted from the plant Ecballium elaterium in order first to assess its in vitro cytotoxicity, but also to study the genetic changes that it could bring out. CucD has shown a blocking in the G1 phase of the cell cycle in NSCLC-N6 cells prior to apoptotic cell death. The reverse transcriptase-polymerase chain reaction-differential display (RT-PCR-DD) technique was also applied on treated cells to elucidate the genetic mechanisms involved. We revealed an overexpression of Cyclin-dependent kinase 1 (CDK1) mRNA after treatment and, with the use of antisense oligonucleotides, an effective role in the proliferation arrest of NSCLC-N6 cells. The present study provides new insights about the mechanisms of proliferation arrest in tumor cells and open new ways of treatment to target tumor growth.

Published
2014

14. CD95L cell surface cleavage triggers a pro-metastatic signaling pathway in triple negative breast cancer

Author

Thomas Ducret, Yves Collette, Marine Malleter, Alban Bessede, Gaëtan MacGrogan, Pierre Vacher, Patrick Legembre, Jean Levêque, Sébastien Tauzin, Florence Godey, Rémy Castellano, Mario Campone, Loïc Campion, Laure Debure, Pascal Jézéquel, Armelle Goubard, Récepteur de mort et échappement tumoral, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service de Biologie, CRLCC Eugène Marquis (CRLCC), Département de Biologie Oncologique, CRLCC René Gauducheau, Centre René Gauducheau, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)

Subjects
Cancer Research, Fas Ligand Protein, Cell, Mice, Transgenic, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, Adenocarcinoma, Biology, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Cell Movement, Mice, Inbred NOD, Tumor Cells, Cultured, medicine, Animals, Humans, Neoplasm Metastasis, Receptor, Triple-negative breast cancer, 030304 developmental biology, 0303 health sciences, Cancer, medicine.disease, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Antigens, Surface, Proteolysis, Immunology, Cancer research, Female, Breast disease, Signal transduction, Reactive Oxygen Species, Carcinogenesis, Signal Transduction
Abstract

Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here, we report that serum levels of CD95 ligand (CD95L) are higher in patients with TNBC than in other patients with breast cancer. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility due to the formation of an unconventional CD95-containing receptosome called the motility-inducing signaling complex. The formation of this complex was instrumental for Nox3-driven reactive oxygen species generation. Mechanistic investigations revealed a Yes–Orai1–EGFR–PI3K pathway that triggered migration of TNBC cells exposed to CD95L. Our findings establish a prometastatic function for metalloprotease-cleaved CD95L in TNBCs, revisiting its role in carcinogenesis. Cancer Res; 73(22); 6711–21. ©2013 AACR.

Published
2013
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15. miRNAs, a potential target in the treatment of Non-Small-Cell Lung Carcinomas

Author

Catherine Jacquot, Christophe Tomasoni, Alain Pineau, Christos Roussakis, Vehary Sakanian, Marine Malleter, Marcel Juge, and Bénédicte Rousseau

Subjects
Lung Neoplasms, RNA, Untranslated, Computational biology, Biology, medicine.disease_cause, Real-Time Polymerase Chain Reaction, MiRBase, Exon, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, microRNA, Genetics, medicine, Gene silencing, Humans, Lung cancer, Gene, Adaptor Proteins, Signal Transducing, Deoxyribonucleases, Gene Expression Profiling, Cell Cycle, RNA, General Medicine, medicine.disease, Phosphoproteins, respiratory tract diseases, Gene Expression Regulation, Neoplastic, MicroRNAs, Carcinogenesis
Abstract

Lung cancer is a serious public health problem and Non Small Cell Lung Carcinoma, NSCLC, is particularly resistant to current treatments. So it is important to find new strategies that are active against NSCLC. miRNA is implicated in cancer and may be implicated in NSCLC. Our team has been working on two genes HEF1, a gene implicated in different functions of cell cycle and B2, a large non-coding RNA (nc RNA). These two genes have the same localisation: chromosome 6 and locus p24–25. nc RNA B2 may be involved in the regulation of HEF1. Firstly, we examine a bank of different human miRNAs known to interact with exons of HEF1. HEF1 and B2 were overexpressed in vitro by treating NSCLC-N6 with the cytostatic molecule A190, and carried out qRT-PCR for the expression of miRNA. Secondly, using specific software, we sought for structures originating from the B2 RNA sequence which might interact with HEF1 and assessed their expression. This strategy enabled us to confirm firstly that known miRNAs that can interact with exons of HEF1 are expressed in NSCLC-N6 cells. More precisely this strategy highlighted overexpression of one miRNA, hsa-miR-146b, listed in miRbase. The second step of the studies highlighted the expression of miRNA, potentially sequences originating from B2 in the NSCLC-N6. This miRNA overexpressed might be one of the regulators of the gene HEF1 and consequently implies on the carcinogenesis of lung cancer. So in the future it could be a potential and an innovative way to find a new strategy for the treatment of lung cancer.

Published
2012

16. A novel large regulator RNA, B2, partially overlaps the HEF1/NEDD9/Cas-L gene

Author

Christos Roussakis, Dimitri Moreau, Patrice Le Pape, Christophe Tomasoni, Ioanna Chinou, Catherine Jacquot, Marianna Tsvetanova, Marcel Juge, Alain Pineau, and Marine Malleter

Subjects
Cell Nucleus, Genetics, RNA, Untranslated, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Intron, RNA, General Medicine, Biology, Phosphoproteins, Non-coding RNA, Antisense RNA, Gene Expression Regulation, Neoplastic, RNA silencing, Exon, RNA editing, Cell Line, Tumor, Humans, Base Pairing, Small nuclear RNA, Adaptor Proteins, Signal Transducing
Abstract

The non-coding RNAs are new players in cellular and molecular biology. Indeed, quantitative and functional non-coding RNA has long been underestimated. There is a great diversity and it seems that much of the genome is transcribed into RNA, while only 1.2% of DNA information is translated into proteins. Non-coding RNA has been categorized according to different specifications so large non-coding RNA includes RNA with 300 to more than 10,000 bp. In this study, we propose a new non-coding RNA named B2 discovered by differential display. B2 is a nuclear RNA which is 51,011 bp long with no significant open reading frame. This RNA has a continuous homology with the genomic DNA of the HEF1/ NEDD9/Cas-L gene located on 6p24-p25. This homology has enabled us to characterize its structure by choosing overlapping fragments to perform several RT-PCRs. B2 RNA extends from 10 kb upstream of exon 1 of the HEF1 gene on the 5' end to exon 4 HEF1 on the 3' end. In addition, a strategic choice of PCR primers enabled us to determine the location of B2 in the subcellular compartment and then real-time PCR revealed overexpression of B2 and HEF1 in certain tissues such as thymus, cervix, liver, and spleen (among the 20 tissues analysed). B2 seems especially interesting in that it can regulate apoptosis and cell proliferation by modulating HEF1. In addition, the fact that cytostatic treatments can induce B2 reinforces the interest in this new potential target in the development of anticancer treatments. These results show that this novel non-coding RNA is an attractive target.

Published
2010
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