PMID- 34297412
OWN - NLM
STAT- MEDLINE
DCOM- 20220119
LR  - 20220119
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 74
IP  - 6
DP  - 2021 Dec
TI  - Zinc Finger E-Box Binding Homeobox 1 Promotes Cholangiocarcinoma Progression 
      Through Tumor Dedifferentiation and Tumor-Stroma Paracrine Signaling.
PG  - 3194-3212
LID - 10.1002/hep.32069 [doi]
AB  - BACKGROUND AND AIMS: Zinc finger E-box 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-associated fibroblasts (CAFs). We aimed to define ZEB1 
      regulatory functions in malignant and stromal compartments of CCA. APPROACH AND 
      RESULTS: Bioinformatic and immunohistochemical analyses were performed to 
      determine correlations between ZEB1 and markers of progressiveness in human 
      intrahepatic CCA (iCCA). Gain-of-function and loss-of-function models were 
      generated in CCA cells and liver myofibroblasts as a model of CAFs. Conditioned 
      media (CM) was used to unravel tumor-stroma interplay. In vivo experiments were 
      performed using a xenograft CCA model. ZEB1 expression in tumor cells of human 
      iCCA was associated with undifferentiated tumor and vascular invasion. In vitro, 
      ZEB1 promoted epithelial-mesenchymal transition and stemness in tumor cells, 
      leading to cell migration and spheroid formation. In vivo, ZEB1-overexpressing 
      CCA cells formed larger tumors with more abundant stroma. Expression of cellular 
      communication network factor 2 (CCN2, encoding connective tissue growth factor 
      [CTGF]) was increased in tumor cells from ZEB1-overexpressing xenografts and 
      correlated with ZEB1 expression in human tumors. In vitro, CM from 
      ZEB1-overexpressing tumor cells or recombinant CTGF induced myofibroblast 
      proliferation. ZEB1 was also expressed by CAFs in human CCA, and its expression 
      correlated with CCN2 in myofibroblasts and CCA stroma. In mice, cotransplantation 
      of CCA cells with ZEB1-depleted myofibroblasts reduced CCA progressiveness 
      compared to CCA cells/ZEB1-expressing myofibroblasts. Furthermore, ZEB1 controls 
      the expression of paracrine signals (i.e., HGF and IL6) in tumor cells and 
      myofibroblasts. CONCLUSIONS: ZEB1 plays a key role in CCA progression by 
      regulating tumor cell-CAF crosstalk, leading to tumor dedifferentiation and CAF 
      activation.
CI  - (c) 2021 by the American Association for the Study of Liver Diseases.
FAU - Lobe, Cindy
AU  - Lobe C
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
FAU - Vallette, Marie
AU  - Vallette M
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
FAU - Arbelaiz, Ander
AU  - Arbelaiz A
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
FAU - Gonzalez-Sanchez, Ester
AU  - Gonzalez-Sanchez E
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
AD  - TGF-beta and Cancer Group, Oncobell Program, Bellvitge Biomedical Research 
      Institute, Barcelona, Spain.
AD  - National Biomedical Research Institute on Liver and Gastrointestinal Diseases 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
FAU - Izquierdo, Laura
AU  - Izquierdo L
AD  - National Biomedical Research Institute on Liver and Gastrointestinal Diseases 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research 
      Institute-Donostia University Hospital, University of the Basque Country, San 
      Sebastian, Spain.
FAU - Pellat, Anna
AU  - Pellat A
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
FAU - Guedj, Nathalie
AU  - Guedj N
AD  - Service d'Anatomie Pathologique Hopital Beaujon, Clichy, France.
FAU - Louis, Corentin
AU  - Louis C
AD  - INSERM, UMR 1149, Centre de Recherche sur l'Inflammation, Paris, France.
FAU - Paradis, Valerie
AU  - Paradis V
AD  - Service d'Anatomie Pathologique Hopital Beaujon, Clichy, France.
AD  - INSERM, UMR 1149, Centre de Recherche sur l'Inflammation, Paris, France.
FAU - Banales, Jesus M
AU  - Banales JM
AD  - National Biomedical Research Institute on Liver and Gastrointestinal Diseases 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research 
      Institute-Donostia University Hospital, University of the Basque Country, San 
      Sebastian, Spain.
AD  - IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
FAU - Coulouarn, Cedric
AU  - Coulouarn C
AD  - Inserm UMR 1241, Universite Rennes 1, Rennes, France.
FAU - Housset, Chantal
AU  - Housset C
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
AD  - Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, 
      Assistance Publique-Hopitaux de Paris, Saint-Antoine Hospital, ERN Rare-Liver, 
      Paris, France.
FAU - Vaquero, Javier
AU  - Vaquero J
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
AD  - TGF-beta and Cancer Group, Oncobell Program, Bellvitge Biomedical Research 
      Institute, Barcelona, Spain.
AD  - National Biomedical Research Institute on Liver and Gastrointestinal Diseases 
      (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
AD  - LPP, Sorbonne Universite, CNRS, Ecole Polytechnique, Universite Paris-Sud, 
      Observatoire de Paris, Universite Paris-Saclay, PSL Research University, Paris, 
      France.
FAU - Fouassier, Laura
AU  - Fouassier L
AUID- ORCID: 0000-0001-6377-5610
AD  - Sorbonne Universite, Inserm, Centre de Recherche Saint-Antoine, Paris, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210928
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (CCN2 protein, human)
RN  - 0 (ZEB1 protein, human)
RN  - 0 (Zinc Finger E-box-Binding Homeobox 1)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
SB  - IM
MH  - Animals
MH  - Bile Duct Neoplasms/*metabolism/pathology
MH  - Cancer-Associated Fibroblasts/*metabolism/pathology
MH  - *Cell Dedifferentiation
MH  - Cholangiocarcinoma/*metabolism/pathology
MH  - Connective Tissue Growth Factor/metabolism
MH  - Epithelial-Mesenchymal Transition
MH  - Humans
MH  - Mice
MH  - Neoplasm Invasiveness
MH  - Neoplasm Transplantation
MH  - *Paracrine Communication
MH  - Stromal Cells
MH  - Zinc Finger E-box-Binding Homeobox 1/*metabolism
EDAT- 2021/07/24 06:00
MHDA- 2022/01/20 06:00
CRDT- 2021/07/23 12:34
PHST- 2021/06/29 00:00 [revised]
PHST- 2020/07/15 00:00 [received]
PHST- 2021/07/11 00:00 [accepted]
PHST- 2021/07/24 06:00 [pubmed]
PHST- 2022/01/20 06:00 [medline]
PHST- 2021/07/23 12:34 [entrez]
AID - 10.1002/hep.32069 [doi]
PST - ppublish
SO  - Hepatology. 2021 Dec;74(6):3194-3212. doi: 10.1002/hep.32069. Epub 2021 Sep 28.