Carcinogenesis Advance Access published online on July 8, 2006
Carcinogenesis, doi:10.1093/carcin/bgl120
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1 CNRS UMR5203, Montpellier, F-34094 France; INSERM, U661, Montpellier, F-34094 France; Univ Montpellier I, Montpellier, F-34094 France; Univ Montpellier II, Montpellier, F-34094 France; Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille, Montpellier F-34094 Cedex 5, France
* To whom correspondence should be addressed. The expression pattern of tight junction (TJ) proteins is frequently disrupted in epithelial tumors. In particular, isoform- and organ-specific alterations of claudins have been detected in human cancers, highlighting them as interesting tools for the prognosis or treatment of various carcinomas. However, the molecular mechanisms responsible for these alterations are seldom identified. Here, we analyzed the expression and localization of claudin-1-4, and -7 in human bladder carcinoma. Claudin-4 expression was significantly altered in 26/39 tumors, contrasting with the rare modifications detected in the expression of claudin-1 and -7. Overexpression of claudin-4 in differentiated carcinomas was followed by a strong down-regulation in invasive/high-grade tumors, and this expression pattern was associated to the one-year survival of bladder tumor patients. A CpG island was identified within the coding sequence of the claudin-4 gene, and treatment with a methyl-transferase inhibitor restored expression of the protein in primary cultures prepared from high-grade human bladder tumors. In addition, claudin-4 expression correlated with its gene methylation profile in healthy and tumoral bladders from 20 patients, and down-regulation of claudin-4 expression was detected in the urothelium of mice overexpressing DNA methyl transferase 3a. Delocalization of claudin-4 and claudin-1 from TJs was observed in most human bladder tumors and in the bladder tumor cell line HT-1376. Although the claudin-4 gene was unmethylated in these cells, pharmacological inhibition of methyl transferases re-addressed the two proteins to TJs, resulting in an increase of cell polarization and trans-epithelial resistance. These biological effects were prevented by expression of claudin-4 specific siRNAs, demonstrating the important role played by claudin-4 in maintaining a functional regulation of homeostasis in urothelial cells. Results of this study indicate that the TJ barrier is disrupted from early stages of urothelial tumorigenesis. In addition, we identified hypermethylation as the mechanism leading to the alteration of claudin-4 expression, and maybe also localization, in bladder carcinoma.
Received March 11, 2006
Revised June 4, 2006
Accepted June 30, 2006
CANCER BIOLOGY
DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma
Stéphanie Boireau 1 *,
Michael Buchert 1 *,
Michael S. Samuel 2,
Julie Pannequin 1,
Joanne L. Ryan 3,
Armelle Choquet 1,
Héliette Chapuis 4,
Xavier Rebillard 5,
Christophe Avancès 6,
Matthias Ernst 2,
Dominique Joubert 1,
Nicolas Mottet 7,
and
Frédéric Hollande 1 *
2 Ludwig Institute for Cancer Research, Parkville, Vic 3050, Australia
3 CNRS UMR5203, Montpellier, F-34094 France; INSERM, U661, Montpellier, F-34094 France; Univ Montpellier I, Montpellier, F-34094 France; Univ Montpellier II, Montpellier, F-34094 France; Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille, Montpellier F-34094 Cedex 5, France; Current address: J.L.R., UMR CNRS 5810, Faculté de Pharmacie, Montpellier, France
4 Service d'Anatomo-pathologie, CHU Groupe Hospitalisation Carémeau, Nîmes, France
5 Service d'Urologie, Clinique Mutualiste BeauSoleil, 34000 Montpellier, France
6 Service d'Urologie, CHU Groupe Hospitalisation Carémeau, Nîmes, France; Service d'Urologie, Polyclinique Kennedy, 30000 Nîmes, France
7 Service d'Urologie, CHU Groupe Hospitalisation Carémeau, Nîmes, France; Current address: N.M., Service d'Urologie, Clinique Mutualiste, St Etienne, France
Frédéric Hollande, E-mail: frederic.hollande{at}univ-montp1.fr
Abstract
* These authors contributed equally to the present work.
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