{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T07:37:30Z","timestamp":1790753850320,"version":"4.1.0"},"reference-count":74,"publisher":"American Society for Clinical Investigation","issue":"16","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,10,6]]},"abstract":"<jats:p>\n                    Aberrant wnt\/\u03b2-catenin signaling and amplification\/overexpression of Myc are associated with hepatoblastoma (HB), the most prevalent type of childhood liver cancer. To address their roles in the pathogenesis of HB, we generated mice in which Myc and mutant \u03b2-catenin were targeted to immature cells of the developing mouse liver. Perinatal coexpression of both genes promoted the preferential development of HBs over other tumor types in neonatal mice, all of which bore striking resemblance to their human counterparts. Integrated analysis indicated that tumors emerged as a consequence of Myc-driven alterations in hepatoblast fate in a background of pan-hepatic injury, inflammation, and nuclear factor (erythroid-derived 2)-like 2\/Nrf2-dependent antioxidant signaling, which was specifically associated with expression of mutant \u03b2-catenin but not Myc. Immunoprofiling of human HBs confirmed that approximately 50% of tumors demonstrated aberrant activation of either Myc or Nfe2l2\/Nrf2, while knockdown of Nrf2 in a cell line\u2013derived from a human HB with\n                    <jats:italic>NFE2L2<\/jats:italic>\n                    gene amplification reduced tumor cell growth and viability. Taken together, these data indicate that \u03b2-catenin creates a protumorigenic hepatic environment in part by indirectly activating Nrf2 and implicate oxidative stress as a possible driving force for a subset of \u03b2-catenin\u2013driven liver tumors in children.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.88549","type":"journal-article","created":{"date-parts":[[2016,10,5]],"date-time":"2016-10-05T11:06:06Z","timestamp":1475665566000},"source":"Crossref","is-referenced-by-count":28,"title":["Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant \u03b2-catenin"],"prefix":"10.1172","volume":"1","author":[{"given":"Sarah A.","family":"Comerford","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Hinnant","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics and"},{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hima","family":"Bansal","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Klapproth","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Rakheja","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milton J.","family":"Finegold","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Lopez-Terrada","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"},{"name":"Department of Pediatrics, Baylor College of Medicine, Texas Children\u2019s Hospital, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn A.","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology,"},{"name":"Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail E.","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA."},{"name":"Department of Pediatrics, University of Texas Health Science Center at San Antonio and Greehey Children\u2019s Cancer Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2016,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2007-2964"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23169"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24219"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/BF00305783"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1978.159"},{"key":"B6"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.24215"},{"issue":"2","key":"B8","first-page":"269","article-title":"Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene","volume":"59","author":"Koch","year":"1999","journal-title":"Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007898"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27243"},{"issue":"8","key":"B11","first-page":"3245","article-title":"Hepatomegaly in transgenic mice expressing an oncogenic form of beta-catenin","volume":"61","author":"Cadoret","year":"2001","journal-title":"Cancer Res"},{"issue":"7","key":"B12","first-page":"1971","article-title":"Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin","volume":"62","author":"Harada","year":"2002","journal-title":"Cancer Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.08.009"},{"issue":"2","key":"B14","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/gcc.20227","article-title":"Cytogenetic evaluation of a large series of hepatoblastomas: numerical abnormalities with recurring aberrations involving 1q12-q21","volume":"44","author":"Tomlinson","year":"2005","journal-title":"Genes Chromosomes Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.11.002"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nature03043"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0020332"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2008.10.018"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64590-7"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2009.06.939"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0029(19971201)39:5<413::AID-JEMT4>3.0.CO;2-H"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009009107"},{"key":"B23","doi-asserted-by":"crossref","DOI":"10.1038\/oncsis.2012.27","article-title":"Comparative analysis of SV40 17kT and LT function in vivo demonstrates that LT\u2019s C-terminus re-programs hepatic gene expression and is necessary for tumorigenesis in the liver","volume":"1","author":"Comerford","year":"2012","journal-title":"Oncogenesis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000258200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1101\/gad.225680.113"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/nature10189"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.08.003"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.2350\/10-09-0900-OA.1"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.22187"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235122"},{"issue":"1","key":"B31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/hep.21952","article-title":"Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate","volume":"47","author":"Decaens","year":"2008","journal-title":"Hepatology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.06.018"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2014.05.004"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/embr.201338254"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003638"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-3275"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.2911736"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1947"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2256"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3252"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3126"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2012.10.001"},{"issue":"14","key":"B43","first-page":"3032","article-title":"Increased risk of hepatoblastoma among immature children with a lower birth weight","volume":"58","author":"Tanimura","year":"1998","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25128"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1080\/10715760290006510"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201000067"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1513\/pats.201201-004MS"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-3064"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080976"},{"issue":"5 Pt 1","key":"B50","first-page":"G874","article-title":"III. Intracellular signaling in response to toxic liver injury","volume":"275","author":"Jones","year":"1998","journal-title":"Am J Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3835(94)90056-6"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20183"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002493"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.04.006"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.445965"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23747"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601950"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26964"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4161\/cc.7.7.5617"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007653"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3278"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0805778105"},{"issue":"4","key":"B63","first-page":"901","article-title":"Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma","volume":"7","author":"Takayasu","year":"2001","journal-title":"Clin Cancer Res"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2011.06.004"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1177\/0192623315599853"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4107"},{"key":"B67","doi-asserted-by":"crossref","DOI":"10.12688\/f1000research.7879.1","article-title":"Strategically targeting Myc in cancer","author":"Posternak","year":"2016","journal-title":"F1000Res"},{"issue":"6","key":"B68","first-page":"715","article-title":"Oncogene-induced liver neoplasia in transgenic mice","volume":"4","author":"Sandgren","year":"1989","journal-title":"Oncogene"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V"},{"issue":"1","key":"B70","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc Series B Stat Methodol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr671"},{"key":"B72","article-title":"Gene expression analysis via multidimensional scaling","volume":"Chapter 7","author":"Chen","year":"2005","journal-title":"Curr Protoc Bioinformatics"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/88549\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:32:52Z","timestamp":1779201172000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/88549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,6]]},"references-count":74,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2016,10,6]]},"published-print":{"date-parts":[[2016,10,6]]}},"alternative-id":["10.1172\/jci.insight.88549"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.88549","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,6]]},"article-number":"e88549"}}