β-Catenin Sustains and Is Required for YES-associated Protein Oncogenic Activity in Cholangiocarcinoma.

Adaptor Proteins, Signal Transducing / genetics Animals Bile Duct Neoplasms / genetics Bile Ducts, Intrahepatic / pathology Carcinogenesis Cholangiocarcinoma / genetics Humans Mice Proto-Oncogene Proteins c-akt / metabolism Transcription Factors / genetics YAP-Signaling Proteins / genetics beta Catenin / genetics
Hippo/YAP Intrahepatic Cholangiocarcinoma TEADs β-Catenin

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
08 2022
Historique:
received: 26 08 2021
revised: 05 04 2022
accepted: 19 04 2022
pubmed: 1 5 2022
medline: 27 7 2022
entrez: 30 4 2022
Statut: ppublish

Résumé

YES-associated protein (YAP) aberrant activation is implicated in intrahepatic cholangiocarcinoma (iCCA). Transcriptional enhanced associate domain (TEAD)-mediated transcriptional regulation is the primary signaling event downstream of YAP. The role of Wnt/β-Catenin signaling in cholangiocarcinogenesis remains undetermined. Here, we investigated the possible molecular interplay between YAP and β-Catenin cascades in iCCA. Activated AKT (Myr-Akt) was coexpressed with YAP (YapS127A) or Tead2VP16 via hydrodynamic tail vein injection into mouse livers. Tumor growth was monitored, and liver tissues were collected and analyzed using histopathologic and molecular analysis. YAP, β-Catenin, and TEAD interaction in iCCAs was investigated through coimmunoprecipitation. Conditional Ctnnb1 knockout mice were used to determine β-Catenin function in murine iCCA models. RNA sequencing was performed to analyze the genes regulated by YAP and/or β-Catenin. Immunostaining of total and nonphosphorylated/activated β-Catenin staining was performed in mouse and human iCCAs. We discovered that TEAD factors are required for YAP-dependent iCCA development. However, transcriptional activation of TEADs did not fully recapitulate YAP's activities in promoting cholangiocarcinogenesis. Notably, β-Catenin physically interacted with YAP in human and mouse iCCA. Ctnnb1 ablation strongly suppressed human iCCA cell growth and Yap-dependent cholangiocarcinogenesis. Furthermore, RNA-sequencing analysis revealed that YAP/ transcriptional coactivator with PDZ-binding motif (TAZ) regulate a set of genes significantly overlapping with those controlled by β-Catenin. Importantly, activated/nonphosphorylated β-Catenin was detected in more than 80% of human iCCAs. YAP induces cholangiocarcinogenesis via TEAD-dependent transcriptional activation and interaction with β-Catenin. β-Catenin binds to YAP in iCCA and is required for YAP full transcriptional activity, revealing the functional crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis.

Sections du résumé

BACKGROUND & AIMS
YES-associated protein (YAP) aberrant activation is implicated in intrahepatic cholangiocarcinoma (iCCA). Transcriptional enhanced associate domain (TEAD)-mediated transcriptional regulation is the primary signaling event downstream of YAP. The role of Wnt/β-Catenin signaling in cholangiocarcinogenesis remains undetermined. Here, we investigated the possible molecular interplay between YAP and β-Catenin cascades in iCCA.
METHODS
Activated AKT (Myr-Akt) was coexpressed with YAP (YapS127A) or Tead2VP16 via hydrodynamic tail vein injection into mouse livers. Tumor growth was monitored, and liver tissues were collected and analyzed using histopathologic and molecular analysis. YAP, β-Catenin, and TEAD interaction in iCCAs was investigated through coimmunoprecipitation. Conditional Ctnnb1 knockout mice were used to determine β-Catenin function in murine iCCA models. RNA sequencing was performed to analyze the genes regulated by YAP and/or β-Catenin. Immunostaining of total and nonphosphorylated/activated β-Catenin staining was performed in mouse and human iCCAs.
RESULTS
We discovered that TEAD factors are required for YAP-dependent iCCA development. However, transcriptional activation of TEADs did not fully recapitulate YAP's activities in promoting cholangiocarcinogenesis. Notably, β-Catenin physically interacted with YAP in human and mouse iCCA. Ctnnb1 ablation strongly suppressed human iCCA cell growth and Yap-dependent cholangiocarcinogenesis. Furthermore, RNA-sequencing analysis revealed that YAP/ transcriptional coactivator with PDZ-binding motif (TAZ) regulate a set of genes significantly overlapping with those controlled by β-Catenin. Importantly, activated/nonphosphorylated β-Catenin was detected in more than 80% of human iCCAs.
CONCLUSION
YAP induces cholangiocarcinogenesis via TEAD-dependent transcriptional activation and interaction with β-Catenin. β-Catenin binds to YAP in iCCA and is required for YAP full transcriptional activity, revealing the functional crosstalk between YAP and β-Catenin pathways in cholangiocarcinogenesis.

Identifiants

DOI: 10.1053/j.gastro.2022.04.028 PMID: 35489428 PMC: PMC9329198
pubmed: 35489428
pii: S0016-5085(22)00440-1
doi: 10.1053/j.gastro.2022.04.028
pmc: PMC9329198
mid: NIHMS1802311
pii:
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
CTNNB1 protein, human 0
Transcription Factors 0
YAP-Signaling Proteins 0
YAP1 protein, human 0
beta Catenin 0
Proto-Oncogene Proteins c-akt EC 2.7.11.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

481-494

Subventions

Organisme : NCI NIH HHS
ID : R01 CA258449
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK026743
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251155
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA250227
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228483
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK132710
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204586
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190606
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Auteurs

Yi Zhang (Y)

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.

Hongwei Xu (H)

Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Guofei Cui (G)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.

Binyong Liang (B)

Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Xiangzheng Chen (X)

Liver Transplantation Division, Department of Liver Surgery, and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.

Sungjin Ko (S)

Department of Pathology and Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Silvia Affo (S)

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Xinhua Song (X)

School of Traditional Chinese Medicine, Capital Medical University, Beijing, China.

Yi Liao (Y)

The Central Laboratory, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, China.

Jianguo Feng (J)

Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, China; Laboratory of Anesthesiology, Southwest Medical University, Luzhou, China.

Pan Wang (P)

Collaborative Innovation Center for Agricultural Product Processing and Nutrition & Health, Beijing Vegetable Research Center, Beijing Academy of Agriculture and Forestry Science, Beijing, China.

Haichuan Wang (H)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Liver Transplantation Division, Department of Liver Surgery, and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.

Meng Xu (M)

Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China.

Jingxiao Wang (J)

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.

Giovanni M Pes (GM)

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

Silvia Ribback (S)

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

Yong Zeng (Y)

Liver Transplantation Division, Department of Liver Surgery, and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.

Aatur Singhi (A)

Department of Pathology and Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Robert F Schwabe (RF)

Department of Medicine, Columbia University, New York, New York.

Satdarshan P Monga (SP)

Department of Pathology and Medicine, and Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Matthias Evert (M)

Institute of Pathology, University of Regensburg, Regensburg, Germany.

Liling Tang (L)

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. Electronic address: tangliling@cqu.edu.cn.

Diego F Calvisi (DF)

Institute of Pathology, University of Regensburg, Regensburg, Germany. Electronic address: diego.calvisi@klinik.uni-regensburg.de.

Xin Chen (X)

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, Hawaii. Electronic address: xinchen3@hawaii.edu.

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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 › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Eucaryotes › Animaux › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Maladies de l'appareil digestif › Tumeurs de l'appareil digestif › Tumeurs des voies biliaires › Tumeurs des canaux biliaires › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Système digestif › Foie › Conduits biliaires intrahépatiques › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Adénocarcinome › Cholangiocarcinome › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-akt › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › β-Catenin Sustains and Is Required for...
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 › β-Catenin Sustains and Is Required for...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › bêta-Caténine › β-Catenin Sustains and Is Required for...