DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma
Identifieur interne : 009655 ( Main/Exploration ); précédent : 009654; suivant : 009656DNA-methylation-dependent alterations of claudin-4 expression in human bladder carcinoma
Auteurs : Stéphanie Boireau [France] ; Michael Buchert [France] ; Michael S. Samuel [Australie] ; Julie Pannequin [France] ; Joanne L. Ryan [France] ; Armelle Choquet [France] ; Héliette Chapuis [France] ; Xavier Rebillard [France] ; Christophe Avances [France] ; Matthias Ernst [Australie] ; Dominique Joubert [France] ; Nicolas Mottet [France] ; Frédéric Hollande [France]Source :
- Carcinogenesis : (New York. Print) [ 0143-3334 ] ; 2007.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
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.
Affiliations:
- Australie, France
- Languedoc-Roussillon, Occitanie (région administrative)
- Montpellier, Nîmes
- Université Montpellier 1
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Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author><author><name sortKey="Buchert, Michael" sort="Buchert, Michael" uniqKey="Buchert M" first="Michael" last="Buchert">Michael Buchert</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>CNRS UMR5203, INSERM U661, Université Montpellier I, Université Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34094</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author><author><name sortKey="Samuel, Michael S" sort="Samuel, Michael S" uniqKey="Samuel M" first="Michael S." last="Samuel">Michael S. Samuel</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Ludwig Institute for Cancer Research</s1><s2>Parkville, Vic 3050</s2><s3>AUS</s3><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Ludwig Institute for Cancer Research</wicri:noRegion></affiliation></author><author><name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>CNRS UMR5203, INSERM U661, Université Montpellier I, Université Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34094</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author><author><name sortKey="Ryan, Joanne L" sort="Ryan, Joanne L" uniqKey="Ryan J" first="Joanne L." last="Ryan">Joanne L. Ryan</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>CNRS UMR5203, INSERM U661, Université Montpellier I, Université Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34094</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author><author><name sortKey="Choquet, Armelle" sort="Choquet, Armelle" uniqKey="Choquet A" first="Armelle" last="Choquet">Armelle Choquet</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>CNRS UMR5203, INSERM U661, Université Montpellier I, Université Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34094</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author><author><name sortKey="Chapuis, Heliette" sort="Chapuis, Heliette" uniqKey="Chapuis H" first="Héliette" last="Chapuis">Héliette Chapuis</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Service d'Anatomo-pathologie, CHU Groupe Hospitalisation Carémeau</s1><s2>Nîmes</s2><s3>FRA</s3><sZ>7 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Nîmes</settlement></placeName></affiliation></author><author><name sortKey="Rebillard, Xavier" sort="Rebillard, Xavier" uniqKey="Rebillard X" first="Xavier" last="Rebillard">Xavier Rebillard</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Service d'Urologie, Clinique Mutualiste Beausoleil</s1><s2>34000 Montpellier</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34000 Montpellier</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region></placeName></affiliation></author><author><name sortKey="Avances, Christophe" sort="Avances, Christophe" uniqKey="Avances C" first="Christophe" last="Avances">Christophe Avances</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Service d'Urologie, CHU Groupe Hospitalisation Carémeau</s1><s2>Nîmes</s2><s3>FRA</s3><sZ>9 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Nîmes</settlement></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Service d'Urologie, Polyclinique Kennedy</s1><s2>30000 Nîmes</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>30000 Nîmes</wicri:noRegion><wicri:noRegion>Polyclinique Kennedy</wicri:noRegion><wicri:noRegion>30000 Nîmes</wicri:noRegion></affiliation></author><author><name sortKey="Ernst, Matthias" sort="Ernst, Matthias" uniqKey="Ernst M" first="Matthias" last="Ernst">Matthias Ernst</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Ludwig Institute for Cancer Research</s1><s2>Parkville, Vic 3050</s2><s3>AUS</s3><sZ>3 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Ludwig Institute for Cancer Research</wicri:noRegion></affiliation></author><author><name sortKey="Joubert, Dominique" sort="Joubert, Dominique" uniqKey="Joubert D" first="Dominique" last="Joubert">Dominique Joubert</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>CNRS UMR5203, INSERM U661, Université Montpellier I, Université Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34094</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author><author><name sortKey="Mottet, Nicolas" sort="Mottet, Nicolas" uniqKey="Mottet N" first="Nicolas" last="Mottet">Nicolas Mottet</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Service d'Urologie, CHU Groupe Hospitalisation Carémeau</s1><s2>Nîmes</s2><s3>FRA</s3><sZ>9 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Languedoc-Roussillon</region><settlement type="city">Nîmes</settlement></placeName></affiliation></author><author><name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>CNRS UMR5203, INSERM U661, Université Montpellier I, Université Montpellier II, Institut de Génomique Fonctionnelle, Département d'Oncologie Cellulaire et Moléculaire, 141 Rue de la Cardonille</s1><s2>Montpellier 34094</s2><s3>FRA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>11 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>34094</wicri:noRegion><placeName><settlement type="city">Montpellier</settlement><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Languedoc-Roussillon</region><settlement type="city">Montpellier</settlement></placeName><orgName type="university">Université Montpellier 1</orgName></affiliation></author></analytic><series><title level="j" type="main">Carcinogenesis : (New York. Print)</title><title level="j" type="abbreviated">Carcinogenesis : (N. Y., Print)</title><idno type="ISSN">0143-3334</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Carcinogenesis : (New York. Print)</title><title level="j" type="abbreviated">Carcinogenesis : (N. Y., Print)</title><idno type="ISSN">0143-3334</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Bladder cancer</term><term>Bladder carcinoma</term><term>DNA</term><term>Human</term><term>Methylation</term><term>Toxicity</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>DNA</term><term>Méthylation</term><term>Toxicité</term><term>Homme</term><term>Carcinome vessie urinaire</term><term>Cancer vessie</term><term>Claudine 4</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li></country><region><li>Languedoc-Roussillon</li><li>Occitanie (région administrative)</li></region><settlement><li>Montpellier</li><li>Nîmes</li></settlement><orgName><li>Université Montpellier 1</li></orgName></list><tree><country name="France"><region name="Occitanie (région administrative)"><name sortKey="Boireau, Stephanie" sort="Boireau, Stephanie" uniqKey="Boireau S" first="Stéphanie" last="Boireau">Stéphanie Boireau</name></region><name sortKey="Avances, Christophe" sort="Avances, Christophe" uniqKey="Avances C" first="Christophe" last="Avances">Christophe Avances</name><name sortKey="Avances, Christophe" sort="Avances, Christophe" uniqKey="Avances C" first="Christophe" last="Avances">Christophe Avances</name><name sortKey="Buchert, Michael" sort="Buchert, Michael" uniqKey="Buchert M" first="Michael" last="Buchert">Michael Buchert</name><name sortKey="Chapuis, Heliette" sort="Chapuis, Heliette" uniqKey="Chapuis H" first="Héliette" last="Chapuis">Héliette Chapuis</name><name sortKey="Choquet, Armelle" sort="Choquet, Armelle" uniqKey="Choquet A" first="Armelle" last="Choquet">Armelle Choquet</name><name sortKey="Hollande, Frederic" sort="Hollande, Frederic" uniqKey="Hollande F" first="Frédéric" last="Hollande">Frédéric Hollande</name><name sortKey="Joubert, Dominique" sort="Joubert, Dominique" uniqKey="Joubert D" first="Dominique" last="Joubert">Dominique Joubert</name><name sortKey="Mottet, Nicolas" sort="Mottet, Nicolas" uniqKey="Mottet N" first="Nicolas" last="Mottet">Nicolas Mottet</name><name sortKey="Pannequin, Julie" sort="Pannequin, Julie" uniqKey="Pannequin J" first="Julie" last="Pannequin">Julie Pannequin</name><name sortKey="Rebillard, Xavier" sort="Rebillard, Xavier" uniqKey="Rebillard X" first="Xavier" last="Rebillard">Xavier Rebillard</name><name sortKey="Ryan, Joanne L" sort="Ryan, Joanne L" uniqKey="Ryan J" first="Joanne L." last="Ryan">Joanne L. Ryan</name></country><country name="Australie"><noRegion><name sortKey="Samuel, Michael S" sort="Samuel, Michael S" uniqKey="Samuel M" first="Michael S." last="Samuel">Michael S. Samuel</name></noRegion><name sortKey="Ernst, Matthias" sort="Ernst, Matthias" uniqKey="Ernst M" first="Matthias" last="Ernst">Matthias Ernst</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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