{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:55:46Z","timestamp":1790776546235,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec>\n            <jats:title>Background and aims<\/jats:title>\n            <jats:p>Zinc finger E\u2010box binding homeobox 1 (ZEB1) is a transcription factor that promotes metastatic and stem cell features, which has been associated with poor prognosis in cholangiocarcinoma (CCA), a desmoplastic cancer enriched in cancer\u2010associated fibroblasts (CAFs). We aimed to define ZEB1 regulatory functions in malignant and stromal compartments of CCA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Bioinformatic and immunohistochemical analyses were performed to determine correlations between ZEB1 and markers of progressiveness in human intrahepatic CCA (iCCA). Gain\u2010of\u2010function and loss\u2010of\u2010function models were generated in CCA cells and liver myofibroblasts as a model of CAFs. Conditioned media (CM) was used to unravel tumor\u2013stroma interplay. <jats:italic toggle=\"yes\">In vivo<\/jats:italic> experiments were performed using a xenograft CCA model. ZEB1 expression in tumor cells of human iCCA was associated with undifferentiated tumor and vascular invasion. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, ZEB1 promoted epithelial\u2013mesenchymal transition and stemness in tumor cells, leading to cell migration and spheroid formation. <jats:italic toggle=\"yes\">In vivo<\/jats:italic>, ZEB1\u2010overexpressing CCA cells formed larger tumors with more abundant stroma. Expression of cellular communication network factor 2 (<jats:italic toggle=\"yes\">CCN2<\/jats:italic>, encoding connective tissue growth factor [CTGF]) was increased in tumor cells from ZEB1\u2010overexpressing xenografts and correlated with ZEB1 expression in human tumors. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, CM from ZEB1\u2010overexpressing tumor cells or recombinant CTGF induced myofibroblast proliferation. ZEB1 was also expressed by CAFs in human CCA, and its expression correlated with <jats:italic toggle=\"yes\">CCN2<\/jats:italic> in myofibroblasts and CCA stroma. In mice, cotransplantation of CCA cells with ZEB1\u2010depleted myofibroblasts reduced CCA progressiveness compared to CCA cells\/ZEB1\u2010expressing myofibroblasts. Furthermore, ZEB1 controls the expression of paracrine signals (i.e., HGF and IL6) in tumor cells and myofibroblasts.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>ZEB1 plays a key role in CCA progression by regulating tumor cell\u2013CAF crosstalk, leading to tumor dedifferentiation and CAF activation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32069","type":"journal-article","created":{"date-parts":[[2021,7,23]],"date-time":"2021-07-23T09:07:36Z","timestamp":1627031256000},"page":"3194-3212","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":30,"title":["Zinc Finger E\u2010Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression Through Tumor Dedifferentiation and Tumor\u2013Stroma Paracrine Signaling"],"prefix":"10.1097","volume":"74","author":[{"given":"Cindy","family":"Lobe","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9,Inserm,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Vallette","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9,Inserm,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ander","family":"Arbelaiz","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9,Inserm,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Gonzalez\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9,Inserm,Centre de Recherche Saint\u2010Antoine,Paris,France"},{"name":"TGF\u2010\u03b2 and Cancer Group,Oncobell Program,Bellvitge Biomedical Research Institute,Barcelona,Spain"},{"name":"National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBERehd),Instituto de Salud Carlos III,Madrid,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBERehd),Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Health Research Institute\u2013Donostia University Hospital,University of the Basque Country,San Sebasti\u00e1n,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pellat","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9,Inserm,Centre de Recherche Saint\u2010Antoine,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Guedj","sequence":"additional","affiliation":[{"name":"Service d'Anatomie Pathologique H\u00f4pital Beaujon,Clichy,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corentin","family":"Louis","sequence":"additional","affiliation":[{"name":"INSERM,UMR 1149,Centre de Recherche sur l'Inflammation,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Paradis","sequence":"additional","affiliation":[{"name":"Service d'Anatomie Pathologique H\u00f4pital Beaujon,Clichy,France"},{"name":"INSERM,UMR 1149,Centre de Recherche sur l'Inflammation,Paris,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesus M","family":"Banales","sequence":"additional","affiliation":[{"name":"National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBERehd),Instituto de Salud Carlos III,Madrid,Spain"},{"name":"Department of Liver and Gastrointestinal Diseases,Biodonostia Health Research Institute\u2013Donostia University Hospital,University of the Basque Country,San Sebasti\u00e1n,Spain"},{"name":"IKERBASQUE,Basque Foundation for Science,Bilbao,Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Coulouarn","sequence":"additional","affiliation":[{"name":"Inserm UMR 1241,Universit\u00e9 Rennes 1,Rennes,France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Housset","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9,Inserm,Centre de Recherche Saint\u2010Antoine,Paris,France"},{"name":"Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis,Assistance Publique\u2010H\u00f4pitaux de Paris,Saint\u2010Antoine Hospital,ERN 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