The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease.

Adaptor Proteins, Signal Transducing / genetics Animals Bile Duct Neoplasms / genetics Bile Ducts, Intrahepatic / metabolism Carcinoma, Hepatocellular / pathology Cholangiocarcinoma / pathology Hippo Signaling Pathway Humans Mice Protein Serine-Threonine Kinases / genetics Proto-Oncogene Proteins c-akt / metabolism Signal Transduction YAP-Signaling Proteins
AKT Hippo pathway Intrahepatic cholangiocarcinoma Notch TAZ TEAD transcription factors

Journal

Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647

Informations de publication

Date de publication:
03 Jun 2022
Historique:
received: 05 03 2022
accepted: 16 05 2022
entrez: 2 6 2022
pubmed: 3 6 2022
medline: 7 6 2022
Statut: epublish

Résumé

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis.

Sections du résumé

BACKGROUND BACKGROUND
Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined.
METHODS METHODS
We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP.
RESULTS RESULTS
Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis.
CONCLUSIONS CONCLUSIONS
Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis.

Identifiants

DOI: 10.1186/s13046-022-02394-2 PMID: 35655220 PMC: PMC9164528
pubmed: 35655220
doi: 10.1186/s13046-022-02394-2
pii: 10.1186/s13046-022-02394-2
pmc: PMC9164528
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
YAP-Signaling Proteins 0
Protein Serine-Threonine Kinases EC 2.7.11.1
Proto-Oncogene Proteins c-akt EC 2.7.11.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

192

Subventions

Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NIH HHS
ID : R01CA190606
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190606
Pays : United States

Commentaires et corrections

Type : ErratumIn

Informations de copyright

© 2022. The Author(s).

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Auteurs

Antonio Cigliano (A)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.
Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.

Shanshan Zhang (S)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.
Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.

Silvia Ribback (S)

Institute of Pathology, University of Greifswald, Greifswald, Germany.

Sara Steinmann (S)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Marcella Sini (M)

Experimental Pathology Unit, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

Cindy E Ament (CE)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Kirsten Utpatel (K)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Xinhua Song (X)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.
School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.

Jingxiao Wang (J)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.

Maria G Pilo (MG)

Institute of Pathology, University of Greifswald, Greifswald, Germany.

Fabian Berger (F)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Haichuan Wang (H)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.
Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.

Junyan Tao (J)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.

Xiaolei Li (X)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.
Department of Thyroid and Breast Surgery, The 960th Hospital of the PLA, Jinan, 250031, China.

Giovanni M Pes (GM)

Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy.

Serena Mancarella (S)

National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy.

Gianluigi Giannelli (G)

National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy.

Frank Dombrowski (F)

Institute of Pathology, University of Greifswald, Greifswald, Germany.

Matthias Evert (M)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Diego F Calvisi (DF)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Xin Chen (X)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, 513 Parnassus Avenue, San Francisco, CA, USA.
University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

Katja Evert (K)

Institute of Pathology, University of Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany. katja.evert@ukr.de.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Eucaryotes › Animaux › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Maladies de l'appareil digestif › Tumeurs de l'appareil digestif › Tumeurs des voies biliaires › Tumeurs des canaux biliaires › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Système digestif › Foie › Conduits biliaires intrahépatiques › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Cholangiocarcinome › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Hippo › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › The Hippo pathway effector TAZ induces...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › The Hippo pathway effector TAZ induces...