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Featured researches published by Martine Mergey.


Gastroenterology | 2009

Bile Salts Control the Antimicrobial Peptide Cathelicidin Through Nuclear Receptors in the Human Biliary Epithelium

Emilie D'Aldebert; Marie–Jeanne Biyeyeme Bi Mve; Martine Mergey; Dominique Wendum; Delphine Firrincieli; Audrey Coilly; Laura Fouassier; Christophe Corpechot; Raoul Poupon; Chantal Housset; Nicolas Chignard

BACKGROUNDS & AIMS Under normal conditions, the biliary tract is a microbial-free environment. The absence of microorganisms has been attributed to various defense mechanisms that include the physicochemical and signaling actions of bile salts. Here, we hypothesized that bile salts may stimulate the expression of a major antimicrobial peptide, cathelicidin, through nuclear receptors in the biliary epithelium. METHODS The expression of cathelicidin was analyzed in human liver samples by immunostaining and reverse-transcription quantitative polymerase chain reaction. The regulation of cathelicidin expression by the endogenous bile salt, chenodeoxycholic acid, and by the therapeutic bile salt, ursodeoxycholic acid (UDCA), was assessed in human biliary epithelial cells in which endogenous nuclear receptor expression was blunted by siRNA or dominant-negative strategies. RESULTS In the human liver, biliary epithelial cells show intense immunoreactivity for cathelicidin and for the vitamin D receptor. In cultured biliary epithelial cells, chenodeoxycholic acid and UDCA induce cathelicidin expression through 2 different nuclear receptors: the farnesoid X receptor and the vitamin D receptor, respectively. Importantly, vitamin D further increases the induction of cathelicidin expression by both bile salts. In a prototypical inflammatory biliary disease (ie, primary biliary cirrhosis), we document that hepatic expressions of the vitamin D receptor and of cathelicidin significantly increased with UDCA therapy. CONCLUSIONS Our results indicate that bile salts may contribute to biliary tract sterility by controlling epithelial cell innate immunity. They further suggest that in inflammatory biliary diseases, which involve bacterial factors, a strategy systematically combining UDCA with vitamin D would increase therapeutic efficacy.


Journal of Hepatology | 2014

EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition

Audrey Clapéron; Martine Mergey; T.H. Nguyen Ho-Bouldoires; D. Vignjevic; Dominique Wendum; Yves Chrétien; Fatiha Merabtene; A. Frazao; Valérie Paradis; Chantal Housset; Nathalie Guedj; Laura Fouassier

BACKGROUND & AIMS Epithelial-mesenchymal transition (EMT) is a cellular process involved in cancer progression. The first step of EMT consists in the disruption of E-cadherin-mediated adherens junctions. Cholangiocarcinoma (CCA), a cancer with a poor prognosis due to local invasion and metastasis, displays EMT features. EGFR, a receptor tyrosine kinase, plays a major role in CCA progression. The aim of the study was to determine if EMT is induced by EGFR in CCA cells. METHODS In vivo, the expression of E-cadherin was analysed in CCA tumours of 100 patients and correlated with pathological features and EGFR expression, and in a xenograft model in mice treated with gefitinib, an inhibitor of EGFR. In vitro, the regulation of EMT by EGFR was investigated in CCA cell lines. RESULTS In human CCA, a cytoplasmic localization of E-cadherin occurred in 50% of the tumours was associated with the peripheral type of CCA, tumour size, the presence of satellite nodules and EGFR overexpression. In xenografted tumours, E-cadherin displayed a cytoplasmic pattern whereas the treatment of mice with gefitinib restored the membranous expression of E-cadherin. In vitro, EGF induced scattering of CCA cells that resulted from the disruption of adherens junctions. Internalization and decreased expression of E-cadherin, as well as nuclear translocation of β-catenin, were observed in EGF-treated CCA cells. In these cells, EMT-transcription factors (i.e., Slug and Zeb-1) and mesenchymal markers (i.e., N-cadherin and α-SMA) were induced, favoring cell invasiveness through cytoskeleton remodeling. All these effects were inhibited by gefitinib. CONCLUSIONS The EGF/EGFR axis triggers EMT in CCA cells highlighting the key role of this pathway in CCA progression.


Hepatology | 2013

Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor.

Audrey Clapéron; Martine Mergey; Lynda Aoudjehane; Thanh Huong Nguyen Ho‐Bouldoires; Dominique Wendum; Aurélie Prignon; Fatiha Merabtene; Delphine Firrincieli; Christèle Desbois-Mouthon; Olivier Scatton; Filomena Conti; Chantal Housset; Laura Fouassier

Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant desmoplastic environment. Poor prognosis of CCA has been associated with the presence of alpha‐smooth muscle actin (α‐SMA)‐positive myofibroblasts (MFs) in the stroma and with the sustained activation of the epidermal growth factor receptor (EGFR) in tumor cells. Among EGFR ligands, heparin‐binding epidermal growth factor (HB‐EGF) has emerged as a paracrine factor that contributes to intercellular communications between MFs and tumor cells in several cancers. This study was designed to test whether hepatic MFs contributed to CCA progression through EGFR signaling. The interplay between CCA cells and hepatic MFs was examined first in vivo, using subcutaneous xenografts into immunocompromised mice. In these experiments, cotransplantation of CCA cells with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and metastastic dissemination of tumors. These effects were abolished by gefitinib, an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA tissues showed that stromal MFs expressed HB‐EGF, whereas EGFR was detected in cancer cells. In vitro, HLMFs produced HB‐EGF and their conditioned media induced EGFR activation and promoted disruption of adherens junctions, migratory and invasive properties in CCA cells. These effects were abolished in the presence of gefitinib or HB‐EGF‐neutralizing antibody. We also showed that CCA cells produced transforming growth factor beta 1, which, in turn, induced HB‐EGF expression in HLMFs. Conclusion: A reciprocal cross‐talk between CCA cells and myofibroblasts through the HB‐EGF/EGFR axis contributes to CCA progression. (Hepatology 2013; 58:2001–2011)


Carbohydrate Research | 1982

Incompatible blood-group a determinants in tumoral mucins. Isolation of oligosaccharides having a 2-acetamido-2-deoxy-α-d-galactopyranosyl group at the non-reducing end

Annick Paul; Brigitte Hermelin; Martine Mergey; Jacques Picard

Two glycopeptide fractions were obtained from pseudomyxomatous mucins secreted by an ovarian cystadenocarcinoma from a female having blood-group B, and by an appendix tumor from a male having blood-group O. The carbohydrate and amino acid content of these fractions suggests the presence of numerous carbohydrate side-chains linked through O-glycosyl bonds to a peptide core rich in threonine and proline. The two glycopeptide fractions exhibit compatible B- and H-blood-group activities. They are reactive towards Dolichos biflorus lectin and human anti-A agglutinins, and so exhibit an incompatible A activity. Alkali-borohydride degradation of Pronase-digested glycopeptides gave dialyzable oligosaccharides that were purified and shown to possess 2-acetamido-2-deoxygalactitol at the terminal reducing-end. 2-Acetamido-2-deoxyglucose, galactose, fucose, and neuraminic acid were absent, or present, in variable proportions. Four oligosaccharides containing 2-acetamido-2-deoxy-D-galactose residues were reactive towards Dolichos biflorus lectin and human anti-A agglutinins, indicating the presence, at the nonreducing end, of a 2-acetamido-2-deoxy-alpha-D-galactopyranosyl group, responsible for blood-group A activity.


Cancer Research | 2010

Abstract 5205: EBP50, a PDZ-containing protein, regulates EGFR-induced cell scattering and migration in human cancer biliary epithelial cells

Audrey Clapéron; Martine Mergey; Nathalie Guedj; Blandine de Singly; Yves Chrétien; Valérie Paradis; Chantal Housset; Laura Fouassier

Background: Cholangiocarcinoma is the second most frequent primary malignant tumor of the liver, accounting for 10-15% of all primary liver cancers. Cholangiocarcinoma grows at the expense of epithelial cells that line intra- and extra-hepatic bile ducts. The adaptor protein EBP50 (Ezrin-radixin-moesin Binding Phosphoprotein 50) binds and regulates transmembrane transporters and receptors including Epidermal Growth Factor Receptor (EGFR). EBP50 and EGFR are both expressed in the normal biliary epithelium. While EGFR participates in biliary carcinogenesis, implication of EBP50 in this cancer is unknown. The aim of the study was to determine the potential links between EBP50 and EGFR in human biliary carcinoma. Methods: In vitro studies were performed in the human biliary epithelial cell line, Mz-ChA-1, that retains epithelial phenotype and endogenous expression of EBP50 and EGFR. The role of EBP50 was examined using siRNA. Cell scattering and migration were evaluated using E-cadherin immunostaining and Boyden chamber, respectively. For in vivo study, 112 patients (mean age: 59.5±11 years, 55 females and 57 males) who underwent surgical resection for hilar (n=53) and peripheral (n=59) cholangiocarcinoma in one single institution were analyzed retrospectively. Immunohistochemistry on tissue microarrays was performed to assess EBP50 and EGFR expression. Results: EGF activates EGFR and the three main signaling pathways, ERK1/2, STAT3 and Akt, in Mz-ChA-1 biliary cancer cells. Inhibition of EBP50 in EGF-treated cells increases and maintains activation of EGFR, and of ERK1/2 and STAT3 but not Akt. Enhanced EGFR activation in response to EBP50 depletion confers sensitivity to EGFR tyrosine kinase inhibitor, gefitinib. Functionally, upon EGF, EGFR drives cell scattering by inducing disruption of adherens junctions. In addition, EGF activates formation of lamellipodia structures and therefore cell migration. Interestingly, inhibition of EBP50 in non EGF-stimulated cell has the same effects on cell scattering and migration as those observed with EGF alone. Cell dispersion due to EBP50 inhibition is abolished in the presence of gefitinib. Moreover, impact on cell scattering and migration is even greater when both EGF addition and EBP50 siRNA are combined. In vivo, delocalization of EBP50 normally expressed beneath the apical membrane is associated with EGFR expression in human biliary carcinoma tissues (p=0.002). Conclusion: These data provide evidence for an essential role of EBP50 in repressing EGFR-induced signaling pathway and migration. EBP50 at the membrane may be critical to confine cancer progression by preventing migration of biliary cancer cells. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5205.


Hepatology | 2001

Bile acid transport and regulating functions in the human biliary epithelium

Nicolas Chignard; Martine Mergey; Danielle Veissière; Rolland Parc; Jacqueline Capeau; Raoul Poupon; Annick Paul; Chantal Housset


Hepatology | 1999

Permissiveness of human biliary epithelial cells to infection by hepatitis C virus

Marie-Anne Loriot; Jean-Pierre Bronowicki; David Lagorce; Fatima Lakehal; Tiziana Persico; Giovanna Barba; Martine Mergey; C. Vons; Dominique Franco; Jacques Belghiti; Mauro Giacca; Chantal Housset; Christian Bréchot


American Journal of Physiology-gastrointestinal and Liver Physiology | 2007

Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes

Laura Fouassier; Marc Beaussier; Eduardo Schiffer; Colette Rey; Véronique Barbu; Martine Mergey; Dominique Wendum; Patrice Callard; Jean-Yves Scoazec; Elisabeth Lasnier; Bruno Stieger; André Lienhart; Chantal Housset


Gastroenterology | 1997

Regulation of Mucin Secretion in Human Gallbladder Epithelial Cells: Predominant Role of Calcium and Protein Kinase C

Nathalie Dray-Charier; Annick Paul; Laurent Combettes; M Bouin; Martine Mergey; P Balladur; Jacqueline Capeau; Chantal Housset


Hepatology | 1999

Expression of delta F508 cystic fibrosis transmembrane conductance regulator protein and related chloride transport properties in the gallbladder epithelium from cystic fibrosis patients.

Nathalie Dray-Charier; Annick Paul; Jean-Yves Scoazec; Danielle Veissière; Martine Mergey; Jacqueline Capeau; Olivier Soubrane; Chantal Housset

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