DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma
| Autor: | Nicolas Mottet, Frédéric Hollande, Matthias Ernst, Christophe Avances, Stéphanie Boireau, Dominique Joubert, Armelle Choquet, Xavier Rebillard, Michael Buchert, Michael S. Samuel, Julie Pannequin, Joanne Ryan, Heliette Chapuis |
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| Přispěvatelé: | Herrada, Anthony, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ludwig Institute for Cancer Research, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Clinique Beau Soleil [Montpellier], Polyclinique Kennedy, Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Pathology MESH: Base Sequence urologic and male genital diseases medicine.disease_cause MESH: Down-Regulation DNA Methyltransferase 3A Mice MESH: DNA Methylation 0302 clinical medicine MESH: Claudin-4 MESH: RNA Small Interfering Gene expression MESH: Animals DNA (Cytosine-5-)-Methyltransferases Claudin-4 RNA Small Interfering MESH: CpG Islands 0303 health sciences Urinary bladder General Medicine Methylation female genital diseases and pregnancy complications MESH: Urinary Bladder Neoplasms 3. Good health medicine.anatomical_structure 030220 oncology & carcinogenesis DNA methylation MESH: Membrane Proteins MESH: DNA (Cytosine-5-)-Methyltransferases medicine.medical_specialty MESH: Cell Line Tumor Down-Regulation [SDV.CAN]Life Sciences [q-bio]/Cancer Biology 03 medical and health sciences [SDV.CAN] Life Sciences [q-bio]/Cancer Cell Line Tumor [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology medicine Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Urothelium Claudin MESH: Mice 030304 developmental biology MESH: Humans Bladder cancer Base Sequence Membrane Proteins DNA Methylation medicine.disease Urinary Bladder Neoplasms Cancer research CpG Islands Carcinogenesis |
| Zdroj: | Carcinogenesis Carcinogenesis, 2007, 28 (2), pp.246-258. ⟨10.1093/carcin/bgl120⟩ Carcinogenesis, Oxford University Press (OUP), 2007, 28 (2), pp.246-258. ⟨10.1093/carcin/bgl120⟩ |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | International audience; 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 claudins 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 claudins 1 and 7. Overexpression of claudin-4 in differentiated carcinomas was followed by a strong downregulation in invasive/high-grade tumors, and this expression pattern was associated to the 1-year survival of bladder tumor patients. A CpG island was identified within the coding sequence of the CLDN4 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 downregulation of claudin-4 expression was detected in the urothelium of mice overexpressing DNA methyl transferase 3a (Dnmt3a). Delocalization of claudins 1 and 4 from TJs was observed in most human bladder tumors and in the bladder tumor cell line HT-1376. Although the CLDN4 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 transepithelial 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. |
| Databáze: | OpenAIRE |
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