{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T07:20:32Z","timestamp":1780730432439,"version":"3.54.1"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"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":[[2018,5]]},"abstract":"<jats:p>Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT\/enhancer binding protein \u03b1 (C\/EBP\u03b1) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C\/EBP\u03b1\u2010S193A, in a large cohort of human HBL samples, and in Pten\/p53 double knockout mice and found that these cancers are characterized by elevation of C\/EBP\u03b1 that is dephosphorylated at Ser190\/193. We found that dephosphorylated C\/EBP\u03b1 creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C\/EBP\u03b1\u2010dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta\u2010like 1 homolog\u2013positive intranuclear inclusions. We further isolated C\/EBP\u03b1\u2010dependent multinucleated hepatocytes and found that they possess characteristics of tumor\u2010initiating cells, including elevation of stem cell markers. C\/EBP\u03b1\u2010dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C\/EBP\u03b1 into an oncogenic isoform, which further creates preneoplastic foci where hepatocytes dedifferentiate into cancer cells, giving rise to liver cancer. (H<jats:sc>epatology<\/jats:sc> 2018;67:1857\u20101871).<\/jats:p>","DOI":"10.1002\/hep.29677","type":"journal-article","created":{"date-parts":[[2017,11,21]],"date-time":"2017-11-21T09:37:39Z","timestamp":1511257059000},"page":"1857-1871","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":34,"title":["C\/EBP\u03b1\u2010dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer"],"prefix":"10.1097","volume":"67","author":[{"given":"Ashley","family":"Cast","sequence":"first","affiliation":[{"name":"Department of Surgery,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Valanejad","sequence":"additional","affiliation":[{"name":"Department of Surgery,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Surgery,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Surgery,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Pathology,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences,St. Jude Children's Research Hospital,Memphis,TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soona","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Surgery,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai","family":"Timchenko","sequence":"additional","affiliation":[{"name":"Department of Surgery,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,3,25]]},"reference":[{"key":"hep29677-bib-0001-20241017","first-page":"1553","article-title":"YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression","volume":"161","year":"2015","journal-title":"Cell Rep"},{"key":"hep29677-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1101\/gad.1938710","article-title":"Nf2\/Merlin controls progenitor homeostasis and tumorigenesis in the liver","volume":"24","year":"2010","journal-title":"Gen Dev"},{"key":"hep29677-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.cell.2013.09.031","article-title":"Identification of liver cancer progenitors whose malignant progression depends on autocrine IL\u20106 signaling","volume":"155","year":"2013","journal-title":"Cell"},{"key":"hep29677-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1053\/j.gastro.2016.11.048","article-title":"Liver cancer cell of origin, molecular class, and effects on patient prognosis","volume":"152","year":"2017","journal-title":"Gastroenterology"},{"key":"hep29677-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1002\/hep.28988","article-title":"Hepatostat: liver regeneration and normal liver tissue maintenance","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep29677-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1002\/hep.28602","article-title":"Genetic lineage tracing analysis of the cell of origin of hepatotoxin\u2010induced liver tumors in mice","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep29677-bib-0007-20241017","first-page":"579","article-title":"p53\u2010dependent Nestin regulation links tumor suppression to cellular plasticity in liver cancer","volume":"158","year":"2016","journal-title":"Cell"},{"key":"hep29677-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/hep.24712","article-title":"Mature hepatocytes exhibit unexpected plasticity by direct dedifferentiation into liver progenitor cells in culture","volume":"55","year":"2012","journal-title":"Hepatology"},{"key":"hep29677-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1159\/000343863","article-title":"Molecular biology of liver cancer stem cells","volume":"3","year":"2014","journal-title":"Liver Cancer"},{"key":"hep29677-bib-0010-20241017","first-page":"26","article-title":"A comparison of cancer burden and research spending reveals discrepancies in the distribution of research funding","volume":"12","year":"2012","journal-title":"BMC Public Health"},{"key":"hep29677-bib-0011-20241017","first-page":"27","article-title":"Elimination of tumor suppressor proteins during liver carcinogenesis","volume":"1","year":"2015","journal-title":"Cancer Studies and Molecular Medicine"},{"key":"hep29677-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.3748\/wjg.14.1720","article-title":"Tumor suppressor and hepatocellular carcinoma","volume":"14","year":"2008","journal-title":"World J Gastroenterology"},{"key":"hep29677-bib-0013-20241017","first-page":"109","article-title":"Genetic modeling of PIM proteins in cancer: proviral tagging and cooperation with oncogenes, tumor suppressor genes, and carcinogens","volume":"4","year":"2014","journal-title":"Front Oncol"},{"key":"hep29677-bib-0014-20241017","first-page":"341","article-title":"Reciprocal expression of CCAAT\/enhancer binding proteins alpha and beta in hepatoblastomas and its prognostic significance","volume":"17","year":"2007","journal-title":"Oncol Rep"},{"key":"hep29677-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/hep.27593","article-title":"CCAAT\/enhancer binding protein \u03b1 predicts poorer prognosis and prevents energy starvation\u2010induced cell death in hepatocellular carcinoma","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep29677-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.tem.2009.01.005","article-title":"Aging and liver regeneration","volume":"20","year":"2009","journal-title":"Trends Endocrinol Metab"},{"key":"hep29677-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1101\/gad.1183304","article-title":"Liver tumors escape negative control of proliferation via PI3K\/Akt\u2010mediated block of C\/EBP\u03b1 growth inhibitory activity","volume":"18","year":"2004","journal-title":"Genes Dev"},{"key":"hep29677-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1128\/MCB.26.7.2570-2582.2006","article-title":"Cyclin D3 maintains growth\u2010inhibitory activity of C\/EBP\u03b1 by stabilizing C\/EBP\u03b1\u2013cdk2 and C\/EBP\u03b1\u2013Brm complexes","volume":"26","year":"2006","journal-title":"Mol Cell Biol"},{"key":"hep29677-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1172\/JCI41933","article-title":"Elimination of C\/EBP\u03b1 through the ubiquitin\u2013proteasome system promotes the development of liver cancer in mice","volume":"120","year":"2010","journal-title":"J Clin Invest"},{"key":"hep29677-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1002\/hep.26146","article-title":"FXR inhibits gankyrin in mouse livers and prevents development of liver cancer","volume":"57","year":"2013","journal-title":"Hepatology"},{"key":"hep29677-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1093\/carcin\/bgx050","article-title":"FXR\u2013gankyrin axis is involved in development of pediatric liver cancer","volume":"38","year":"2017","journal-title":"Carcinogenesis"},{"key":"hep29677-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/hep.27295","article-title":"Cooperation of C\/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration in mice","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep29677-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/hep.27329","article-title":"Terminating hepatocyte proliferation during liver regeneration: the roles of two members of the same family (C\/EBP \u03b1 and \u03b2) with opposing actions","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep29677-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/hep.21328","article-title":"Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas","volume":"44","year":"2006","journal-title":"Hepatology"},{"key":"hep29677-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.ccr.2008.11.002","article-title":"Hepatic stem\u2010like phenotype and interplay of Wnt\/beta\u2010catenin and Myc signaling in aggressive childhood liver cancer","volume":"14","year":"2008","journal-title":"Cancer Cell"},{"key":"hep29677-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"20471","DOI":"10.1073\/pnas.1009009107","article-title":"Stem cell\u2010like micro\u2010RNA signature driven by Myc in aggressive liver cancer","volume":"107","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep29677-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.jhep.2014.08.009","article-title":"The genomic landscape of hepatoblastoma and their progenies with HCC\u2010like features","volume":"61","year":"2014","journal-title":"J Hepatol"},{"key":"hep29677-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.celrep.2013.02.009","article-title":"Increased expression of enzymes of triglyceride synthesis plays is essential for the development of hepatic steatosis","volume":"3","year":"2013","journal-title":"Cell Rep"},{"key":"hep29677-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1101\/gad.2027811","article-title":"Foxl1\u2010Cre\u2010marked adult hepatic progenitors have clonogenic and bilineage differentiation potential","volume":"25","year":"2011","journal-title":"Genes Dev"},{"key":"hep29677-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.cell.2016.07.045","article-title":"Multi\u2010organ mapping of cancer risk","volume":"166","year":"2016","journal-title":"Cell"},{"key":"hep29677-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1053\/j.gastro.2014.09.039","article-title":"Ablation of Foxl1\u2010Cre\u2010labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury","volume":"148","year":"2015","journal-title":"Gastroenterology"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29677","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.29677","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.29677","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201805000-00027","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:12:57Z","timestamp":1729210377000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201805000-00027"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,25]]},"references-count":31,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29677","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,25]]},"assertion":[{"value":"2017-08-16","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-11-16","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}