{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:27:23Z","timestamp":1790270843615,"version":"4.1.0"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"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":[[2016,10]]},"abstract":"<jats:p>The expression of biliary\/progenitor markers by hepatocellular carcinoma (HCC) is often associated with poor prognosis and stem cell\u2010like behaviors of tumor cells. Hepatocellular adenomas (HCAs) also often express biliary\/progenitor markers and frequently act as precursor lesions for HCC. However, the cell of origin of HCA and HCC that expresses these markers remains unclear. Therefore, to evaluate if mature hepatocytes give rise to HCA and HCC tumors and to understand the molecular pathways involved in tumorigenesis, we lineage\u2010labeled hepatocytes by injecting adeno\u2010associated virus containing thyroxine\u2010binding globulin promoter\u2010driven causes recombination (<jats:italic toggle=\"yes\">AAV\u2010TBG\u2010Cre<\/jats:italic>) into <jats:italic toggle=\"yes\">RosaYFP\n                           <\/jats:italic> mice. Yellow fluorescent protein (YFP) was present in &gt;96% of hepatocytes before exposure to carcinogens. We treated <jats:italic toggle=\"yes\">AAV\u2010TBG\u2010Cre<\/jats:italic>; <jats:italic toggle=\"yes\">RosaYFP\n                           <\/jats:italic> mice with diethylnitrosamine (DEN), followed by multiple injections of carbon tetrachloride to induce carcinogenesis and fibrosis and found that HCA and HCC nodules were YFP<jats:sup>+<\/jats:sup> lineage\u2010labeled; positive for osteopontin, SRY (sex determining region Y)\u2010box 9, and epithelial cell adhesion molecule; and enriched for transcripts of biliary\/progenitor markers such as prominin 1, Cd44, and delta\u2010like 1 homolog. Next, we performed the converse experiment and lineage\u2010labeled forkhead box protein L1(Foxl1)\u2010positive hepatic progenitor cells simultaneously with exposure to carcinogens. None of the tumor nodules expressed YFP, indicating that Foxl1\u2010expressing cells are not the origin for hepatotoxin\u2010induced liver tumors. We confirmed that HCA and HCC cells are derived from mature hepatocytes and not from <jats:italic toggle=\"yes\">Foxl1\u2010Cre<\/jats:italic>\u2010marked cells in a second model of toxin\u2010induced hepatic neoplasia, using DEN and 3,3\u2032,5,5\u2032\u2010tetrachloro\u20101,4\u2010bis(pyridyloxy)benzene (TCPOBOP). <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Hepatocytes are the cell of origin of HCA and HCC in DEN\/carbon tetrachloride and DEN\/TCPOBOP induced liver tumors. (H<jats:sc>epatology<\/jats:sc> 2016;64:1163\u20101177)<\/jats:p>","DOI":"10.1002\/hep.28602","type":"journal-article","created":{"date-parts":[[2016,4,21]],"date-time":"2016-04-21T12:48:42Z","timestamp":1461242922000},"page":"1163-1177","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":79,"title":["Genetic lineage tracing analysis of the cell of origin of hepatotoxin\u2010induced liver tumors in mice"],"prefix":"10.1097","volume":"64","author":[{"given":"Soona","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk J.","family":"Wangensteen","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases,University of Pennsylvania,Philadelphia,PA"},{"name":"Department of Medicine,Division of Gastroenterology,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Teta\u2010Bissett","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue J.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham","family":"Mosleh\u2010Shirazi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth L.","family":"Buza","sequence":"additional","affiliation":[{"name":"Department of Pathobiology,University of Pennsylvania School of Veterinary Medicine,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda E.","family":"Greenbaum","sequence":"additional","affiliation":[{"name":"Departments of Cancer Biology and Medicine,Thomas Jefferson University,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus H.","family":"Kaestner","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases,University of Pennsylvania,Philadelphia,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2016,5,28]]},"reference":[{"key":"hep28602-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/ajg.2014.11","article-title":"Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States","volume":"109","year":"2014","journal-title":"Am J Gastroenterol"},{"key":"hep28602-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1002\/hep.27222","article-title":"Epidemiology of hepatocellular carcinoma in the United States: Where are we? 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