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Hepatitis B virus (<jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content>) infection is one of the main causes of <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>. A high prevalence of pre\u2010S deletions of <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content> surface antigen, which encompass T\u2010cell and\/or B\u2010cell epitopes, is found in <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content> carriers; antiviral therapy and viral immune escape may cause and select for these <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content> mutants. In particular, the presence of pre\u2010<jats:styled-content style=\"fixed-case\">S2<\/jats:styled-content> deletion mutants is an important risk factor associated with cirrhosis and <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>. We generated Alb\u2010pre\u0394<jats:styled-content style=\"fixed-case\">S2<\/jats:styled-content> transgenic mice that express a naturally occurring pre\u2010<jats:styled-content style=\"fixed-case\">S2<\/jats:styled-content> mutant protein containing a 33\u2010nucleotide deletion (pre\u0394<jats:styled-content style=\"fixed-case\">S2<\/jats:styled-content>); the aim was to investigate its effect on hepatocarcinogenesis. After 30 months of follow\u2010up, the liver pathology of the mice fell into four groups: <jats:styled-content style=\"fixed-case\">G1<\/jats:styled-content>, chronic inflammation solely; <jats:styled-content style=\"fixed-case\">G2<\/jats:styled-content>, chronic inflammation and fibrosis; <jats:styled-content style=\"fixed-case\">G3<\/jats:styled-content>, inflammation, fibrosis, and hepatomegaly accompanied by rectal prolapse (4\u201312%); and <jats:styled-content style=\"fixed-case\">G4<\/jats:styled-content>, hepatomegaly and spontaneous <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> (12\u201315%). Striking degeneration of the endoplasmic reticulum (<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>) was present in the mouse livers at an early stage (4\u2009months old). At 8 months, overt <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress and the Atf6 pathway of the unfolded protein response (<jats:styled-content style=\"fixed-case\">UPR<\/jats:styled-content>) were induced; at the same time, metabolic pathways associated with mevalonate and cholesterol biogenesis, involving the peroxisomes and the <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>, were disturbed. At 20 months and older, the protein kinase <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\u2010like endoplasmic reticulum kinase (<jats:styled-content style=\"fixed-case\">PERK<\/jats:styled-content>) pathway of the <jats:styled-content style=\"fixed-case\">UPR<\/jats:styled-content> was induced and the Hippo transducer Yap was activated. Together, these ultrastructural aberrations and metabolic disturbance all seem to contribute to the molecular pathogenesis and hepatocarcinogenesis present in the Alb\u2010pre\u0394<jats:styled-content style=\"fixed-case\">S2<\/jats:styled-content> mice. These findings may contribute to the development of therapies for the liver disorders and <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> associated with pre\u2010<jats:styled-content style=\"fixed-case\">S2<\/jats:styled-content> deletion mutations among <jats:styled-content style=\"fixed-case\">HBV<\/jats:styled-content> carriers. Copyright \u00a9 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4850","type":"journal-article","created":{"date-parts":[[2016,11,21]],"date-time":"2016-11-21T04:02:52Z","timestamp":1479700972000},"page":"463-474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Expression of a hepatitis B virus pre\u2010<scp>S2<\/scp> deletion mutant in the liver results in hepatomegaly and hepatocellular carcinoma in mice"],"prefix":"10.1002","volume":"241","author":[{"given":"Yuan\u2010Chi","family":"Teng","sequence":"first","affiliation":[{"name":"Program in Molecular Medicine, School of Life Sciences National Yang\u2010Ming University and Academia Sinica  Taipei Taiwan"},{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang\u2010Ming University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenq 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