{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:30:32Z","timestamp":1787243432020,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01CA159942"],"award-info":[{"award-number":["R01CA159942"]}]},{"name":"NIH","award":["NIH P30 DK078392"],"award-info":[{"award-number":["NIH P30 DK078392"]}]},{"name":"Internal Development Funds from CCHMC (NT)","award":["R01CA159942"],"award-info":[{"award-number":["R01CA159942"]}]},{"name":"Internal Development Funds from CCHMC (NT)","award":["NIH P30 DK078392"],"award-info":[{"award-number":["NIH P30 DK078392"]}]},{"name":"(Gene Analysis Core and Clinical Component) of the Digestive Diseases Research Core Center in Cincinnati","award":["R01CA159942"],"award-info":[{"award-number":["R01CA159942"]}]},{"name":"(Gene Analysis Core and Clinical Component) of the Digestive Diseases Research Core Center in Cincinnati","award":["NIH P30 DK078392"],"award-info":[{"award-number":["NIH P30 DK078392"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background and Aims: Hepatoblastoma (HBL), a deadly malignancy in children, is the most common type of pediatric liver cancer. We recently demonstrated that \u03b2-catenin, phosphorylated at S675 (ph-S675-\u03b2-catenin), causes pathological alterations in fibrolamellar hepatocellular carcinoma (FLC), by activating oncogenes and fibrotic genes via human genomic regions, known as cancer-enhancing genomic regions or aggressive liver cancer domains (CEGRs\/ALCDs). The aim of this study was to determine the role of the ph-S675-\u03b2-catenin-TCF4-CEGRs\/ALCDs pathway in HBL. Methods: The ph-S675-\u03b2-catenin-TCF4-CEGRs\/ALCDs pathway was examined in a large cohort of HBL specimens, in HBL cell lines HepG2 and Huh6, and in patient-derived xenografts (PDXs). Results: \u03b2-catenin is phosphorylated at S675 in a large portion of tested HBL patients. In these patients, ph-S675-\u03b2-catenin forms complexes with TCF4 and opens CEGRs\/ALCDs-dependent oncogenes for transcription, leading to a massive overexpression of the oncogenes. The inhibition of the \u03b2-catenin-TCF4-CEGRs\/ALCDs axis inhibits the proliferation of cancer cells and tumor growth in HBL cell lines and HBL-PDXs. The ph-S675-\u03b2-catenin is abundant in mitotic cells. We found that markers of HBL Glypican 3 (GPC3) and Alpha Fetoprotein (AFP) are increased in HBL patients by \u03b2-catenin-TCF4-p300 complexes. Conclusions: The phosphorylation-mediated activation of the \u03b2-catenin-TCF4-p300-CEGRs\/ALCDs pathway increases oncogene expression in patients with aggressive liver cancer and promotes the development of hepatoblastoma.<\/jats:p>","DOI":"10.3390\/cancers14246062","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T06:14:00Z","timestamp":1670566440000},"page":"6062","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Phosphorylation-Mediated Activation of \u03b2-Catenin-TCF4-CEGRs\/ALCDs Pathway Is an Essential Event in Development of Aggressive Hepatoblastoma"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6194-9805","authenticated-orcid":false,"given":"Ruhi","family":"Gulati","sequence":"first","affiliation":[{"name":"Division of General and Thoracic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3469-2474","authenticated-orcid":false,"given":"Margaret A.","family":"Hanlon","sequence":"additional","affiliation":[{"name":"Division of General and Thoracic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Lutz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Quitmeyer","sequence":"additional","affiliation":[{"name":"Division of General and Thoracic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Geller","sequence":"additional","affiliation":[{"name":"Department of Oncology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Tiao","sequence":"additional","affiliation":[{"name":"Division of General and Thoracic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubov","family":"Timchenko","sequence":"additional","affiliation":[{"name":"Department of Neurology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai","family":"Timchenko","sequence":"additional","affiliation":[{"name":"Division of General and Thoracic Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA"},{"name":"Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1177\/1093526619875228","article-title":"Hepatoblastoma and Pediatric Hepatocellular Carcinoma: An Update","volume":"23","author":"Ranganathan","year":"2019","journal-title":"Pediatr. 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