Fiche publication
Date publication
janvier 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LEFEBVRE Olivier
,
Dr OREND Gertraud
Tous les auteurs :
Spenle C, Lefebvre O, Lacroute J, Mechine-Neuville A, Barreau F, Blottiere HM, Duclos B, Arnold C, Hussenet T, Hemmerle J, Gullberg D, Kedinger M, Sorokin L, Orend G, Simon-Assmann P
Lien Pubmed
Résumé
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 LMalpha1 and LMalpha5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMalpha1 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 LMalpha1 or LMalpha5 specifically in the intestine. We demonstrated that high LMalpha1 or LMalpha5 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 LMalpha1 and LMalpha5 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.
Référence
PLoS One. 2014 Oct 27;9(10):e111336
