title: The laminin response in inflammatory bowel disease: protection or malignancy?
abstract: Laminins (LM), basement membrane molecules and mediators of epithelial-stromal communication, are crucial in tissue homeostasis. Inflammatory Bowel Diseases (IBD) are multifactorial pathologies where the microenvironment and in particular LM play an important yet poorly understood role in tissue maintenance, and in cancer progression which represents an inherent risk of IBD. Here we showed first that in human IBD colonic samples and in murine colitis the LMα1 and LMα5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMα1 expression at the promoter level by ChIP analysis and this was confirmed by knockdown in cell transfection experiments. To mimic the human disease, we induced colitis and colitis-associated cancer by chemical treatment (DSS) combined or not with a carcinogen (AOM) in transgenic mice overexpressing LMα1 or LMα5 specifically in the intestine. We demonstrated that high LMα1 or LMα5 expression decreased susceptibility towards experimentally DSS-induced colon inflammation as assessed by histological scoring and decrease of pro-inflammatory cytokines. Yet in a pro-oncogenic context, we showed that LM would favor tumorigenesis as revealed by enhanced tumor lesion formation in both LM transgenic mice. Altogether, our results showed that nuclear p53 and associated overexpression of LMα1 and LMα5 protect tissue from inflammation. But in a mutation setting, the same LM molecules favor progression of IBD into colitis-associated cancer. Our transgenic mice represent attractive new models to acquire knowledge about the paradoxical effect of LM that mediate either tissue reparation or cancer according to the microenvironment. In the early phases of IBD, reinforcing basement membrane stability/organization could be a promising therapeutic approach.
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Spenlé
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lefebvre
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Department of Gastroenterology, CHRU Hautepierre, Strasbourg, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Lacroute
authors.affiliation: Department of Anatomy and Pathology, CHRU Hautepierre, Strasbourg, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Méchine-Neuville
authors.affiliation: Inserm U843, Paris, France.
authors.forename: Frédérick
authors.initials: F
authors.lastname: Barreau
authors.affiliation: INRA, UMR1319, Jouy-en-Josas, France; AgroParisTech, UMR Micalis, Jouy-en-Josas, France.
authors.forename: Hervé M
authors.initials: HM
authors.lastname: Blottière
authors.affiliation: Department of Gastroenterology, CHRU Hautepierre, Strasbourg, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Duclos
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Arnold
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hussenet
authors.affiliation: Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France; Inserm U1121, Strasbourg, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hemmerlé
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Donald
authors.initials: D
authors.lastname: Gullberg
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Kedinger
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Gertraud
authors.initials: G
authors.lastname: Orend
authors.affiliation: Inserm U1109, MNT3 team, Strasbourg, France; Université de Strasbourg, Strasbourg, France; LabEx Medalis, Université de Strasbourg, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Simon-Assmann
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002277:Carcinoma / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016207:Cytokines; D007797:Laminin; D016159:Tumor Suppressor Protein p53