{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T06:18:45Z","timestamp":1790489925550,"version":"4.1.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T00:00:00Z","timestamp":1621987200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion\u2010defective preS2 deletion mutant (preS2\u0394MT) on hepatocyte damage <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and liver fibrosis <jats:italic toggle=\"yes\">in vivo<\/jats:italic>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case\u2013control follow\u2010up study. Effects of preS2\u0394MT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072\u20109.613; <jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a00.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133\u20106.873; <jats:italic toggle=\"yes\">P<\/jats:italic>\u00a0=\u00a00.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2\u0394MT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real\u2010time ATP assay, and calcium staining of preS2\u0394MT\u2010expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100\u2010fold lower in preS2\u0394MT\u2010infected humanized Fah\u2013\/\u2013\/ Rag2\u2013\/\u2013\/Il2rg\u2013\/\u2013 triple knockout mice than in wild\u2010type HBV\u2010infected mice. PreS2\u0394MT\u2010infected mice displayed up\u2010regulation of UPR and caspase\u20103 and enhanced liver fibrosis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31789","type":"journal-article","created":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T02:49:27Z","timestamp":1614998967000},"page":"641-655","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":60,"title":["Clinical Implications of HBV PreS\/S Mutations and the Effects of PreS2 Deletion on Mitochondria, Liver Fibrosis, and Cancer Development"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3774-3329","authenticated-orcid":false,"given":"Yuh\u2010Jin","family":"Liang","sequence":"first","affiliation":[{"name":"Translational Research Division,Medical Research Department,Taipei Veterans General Hospital,Taipei,Taiwan, ROC"},{"name":"Cancer Progression Research Center,National Yang\u2010Ming University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology & Hepatology,Chang Gung Memorial Hospital, Linkou Medical Center,Taoyuan,Taiwan, ROC"},{"name":"Institute of Clinical Medicine,National Yang\u2010Ming University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih\u2010Li","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine,College of Medicine,Fu Jen Catholic University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Pu","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences,Academia Sinica,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui\u2010Dung","family":"Teng","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine,National Yang\u2010Ming University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen\u2010Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Systems and Synthetic Biology and Institute of Biomedical Informatics,National Yang\u2010Ming University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kung\u2010Hao","family":"Liang","sequence":"additional","affiliation":[{"name":"Translational Research Division,Medical Research Department,Taipei Veterans General Hospital,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Translational Research Division,Medical Research Department,Taipei Veterans General Hospital,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung\u2010Chih","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences,Yang\u2010Ming University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3889-7004","authenticated-orcid":false,"given":"Chien\u2010Wei","family":"Su","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology,Department of Medicine,Taipei Veterans General Hospital,Taipei,Taiwan, ROC"},{"name":"Faculty of Medicine,School of Medicine,National Yang\u2010Ming University,Taipei,Taiwan, ROC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi\u2010Hua","family":"Tao","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences,Academia Sinica,Taipei,Taiwan, 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