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Nuclear translocation of YAP drives BMI-associated hepatocarcinogenesis in hepatitis B virus infection.
Luo, Xufeng; Zhang, Rui; Schefczyk, Stefan; Liang, Yaojie; Lin, Shu S; Liu, Shi; Baba, Hideo A; Lange, Christian M; Wedemeyer, Heiner; Lu, Mengji; Broering, Ruth.
Afiliação
  • Luo X; Institute for Lymphoma Research, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
  • Zhang R; Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • Schefczyk S; Department of Hepato-Pancreato-Biliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • Liang Y; Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • Lin SS; Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • Liu S; Department of Hepato-Pancreato-Biliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • Baba HA; State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, China.
  • Lange CM; Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
  • Wedemeyer H; Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • Lu M; Department of Internal Medicine II, LMU University Hospital Munich, Munich, Germany.
  • Broering R; Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
Liver Int ; 43(9): 2002-2016, 2023 09.
Article em En | MEDLINE | ID: mdl-37312627
ABSTRACT
BACKGROUND AND

AIMS:

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)-dependent neoplastic transformation.

METHODS:

Liver tissue and hepatocytes from HBsAg-transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV-related HCC biopsies.

RESULTS:

Hepatic expression signatures in HBsAg-transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg-transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16INK4a , p19ARF , p53 and Caspase 3 as well as increased Cyclin D1 and γ-H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual-luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non-tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof-of-concept, treatment of HBsAg-transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1-related cell cycle.

CONCLUSION:

HBV-associated proliferative HCC might be related to the HBsAg-YAP-BMI1 axis and offer a potential target for the development of new therapeutic approaches.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Hepatite B / Neoplasias Hepáticas Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Hepatite B / Neoplasias Hepáticas Idioma: En Ano de publicação: 2023 Tipo de documento: Article