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The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)\u2010dependent neoplastic transformation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Liver tissue and hepatocytes from HBsAg\u2010transgenic 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\u2010related HCC biopsies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatic expression signatures in HBsAg\u2010transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg\u2010transgenic 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 p16<jats:sup>INK4a<\/jats:sup>, p19<jats:sup>ARF<\/jats:sup>, p53 and Caspase 3 as well as increased Cyclin D1 and \u03b3\u2010H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual\u2010luciferase reporter assays confirmed that the YAP\/TEAD4 transcription factor complex bound and activated the <jats:italic>Bmi1<\/jats:italic> promoter. In chronic hepatitis B patients, paired liver biopsies of non\u2010tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof\u2010of\u2010concept, treatment of HBsAg\u2010transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1\u2010related cell cycle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>HBV\u2010associated proliferative HCC might be related to the HBsAg\u2010YAP\u2010BMI1 axis and offer a potential target for the development of new therapeutic approaches.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15628","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T07:08:48Z","timestamp":1686726528000},"page":"2002-2016","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Nuclear translocation of <scp>YAP<\/scp> drives <scp>BMI<\/scp>\u2010associated hepatocarcinogenesis in hepatitis B virus infection"],"prefix":"10.1111","volume":"43","author":[{"given":"Xufeng","family":"Luo","sequence":"first","affiliation":[{"name":"Institute for Lymphoma Research The Affiliated Cancer Hospital of Zhengzhou University &amp; Henan Cancer Hospital  Zhengzhou China"},{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepato\u2010Pancreato\u2010Biliary Surgery, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Schefczyk","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaojie","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu S.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Hepato\u2010Pancreato\u2010Biliary Surgery, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Virology, Modern Virology Research Center College of Life Sciences, Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo A.","family":"Baba","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Essen, University of Duisburg\u2010Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7892-5503","authenticated-orcid":false,"given":"Christian 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