{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:18:10Z","timestamp":1787505490714,"version":"build-2736575974"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K19320"],"award-info":[{"award-number":["15K19320"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Previous studies have shown that phosphorylation of the retinoid X receptor-\u03b1 (RXR\u03b1) is associated with the development of hepatocellular carcinoma (HCC). However, these findings were revealed using HCC cell lines that express phosphorylated-RXR\u03b1 (p-RXR\u03b1) proteins; therefore, it remains unclear whether p-RXR\u03b1 affects hepatocarcinogenesis in vivo. Therefore, to investigate the biological function of p-RXR\u03b1 in vivo, we developed a doxycycline-inducible ES cell line and transgenic mouse, both of which overexpress the phosphomimetic mutant form of RXR\u03b1, T82D\/S260D, in a doxycycline-dependent manner. We found that the development of liver tumors, especially high-grade adenoma and HCC, was enhanced in diethylnitrosamine (DEN)-treated T82D\/S260D-inducible mice. Moreover, the increased incidence of liver tumors in the transgenic mice was attributable to the promotion of cell cycle progression. Interestingly, the expression of \u03b2-catenin protein and its target gene cyclin D1 was elevated in the liver tumors of DEN-treated T82D\/S260D-inducible mice, concurrent with increased cytoplasmic and nuclear \u03b2-catenin protein expression, indicating its stabilization and transcriptional activation. These results indicate that p-RXR\u03b1 promotes DEN-induced hepatocarcinogenesis in mice through the activation of the \u03b2-catenin signaling pathway, suggesting that p-RXR\u03b1 may serve as a possible therapeutic target for HCC.<\/jats:p>","DOI":"10.1093\/carcin\/bgab099","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T06:44:11Z","timestamp":1634625851000},"page":"254-263","source":"Crossref","is-referenced-by-count":9,"title":["The phosphorylated retinoid X receptor-\u03b1 promotes diethylnitrosamine-induced hepatocarcinogenesis in mice through the activation of \u03b2-catenin signaling pathway"],"prefix":"10.1093","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2767-9063","authenticated-orcid":false,"given":"Hiroyasu","family":"Sakai","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Yamada","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Kubota","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Imai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Shirakami","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Hara","sequence":"additional","affiliation":[{"name":"Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahito","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"2022042513024884400_CIT0001","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1056\/NEJMra1001683","article-title":"Hepatocellular carcinoma","volume":"365","author":"El-Serag","year":"2011","journal-title":"N. 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Med.,"},{"key":"2022042513024884400_CIT0005","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S0140-6736(16)32453-9","article-title":"Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"389","author":"Bruix","year":"2017","journal-title":"Lancet,"},{"key":"2022042513024884400_CIT0006","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet,"},{"key":"2022042513024884400_CIT0007","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1096\/fasebj.10.9.8801176","article-title":"A decade of molecular biology of retinoic acid receptors","volume":"10","author":"Chambon","year":"1996","journal-title":"FASEB J.,"},{"key":"2022042513024884400_CIT0008","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S1040-8428(01)00144-5","article-title":"Retinoids and their receptors in cancer development and chemoprevention","volume":"41","author":"Sun","year":"2002","journal-title":"Crit. 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Evol.,"},{"key":"2022042513024884400_CIT0012","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/j.addr.2010.07.003","article-title":"Retinoid pathway and cancer therapeutics","volume":"62","author":"Bushue","year":"2010","journal-title":"Adv. Drug Deliv. Rev.,"},{"key":"2022042513024884400_CIT0013","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/hep.20335","article-title":"Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice","volume":"40","author":"Yanagitani","year":"2004","journal-title":"Hepatology,"},{"key":"2022042513024884400_CIT0014","first-page":"7675","article-title":"Phosphorylation of retinoid X receptor alpha at serine 260 impairs its metabolism and function in human hepatocellular carcinoma","volume":"61","author":"Matsushima-Nishiwaki","year":"2001","journal-title":"Cancer Res.,"},{"key":"2022042513024884400_CIT0015","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1053\/jhep.2002.31164","article-title":"Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma","volume":"35","author":"Adachi","year":"2002","journal-title":"Hepatology,"},{"key":"2022042513024884400_CIT0016","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1093\/carcin\/bgg090","article-title":"Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid","volume":"24","author":"Matsushima-Nishiwaki","year":"2003","journal-title":"Carcinogenesis,"},{"key":"2022042513024884400_CIT0017","doi-asserted-by":"crossref","first-page":"6710","DOI":"10.1158\/1078-0432.CCR-04-0659","article-title":"Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells","volume":"10","author":"Shimizu","year":"2004","journal-title":"Clin. Cancer Res.,"},{"key":"2022042513024884400_CIT0018","first-page":"3997","article-title":"Growth inhibition of human hepatoma cells by acyclic retinoid is associated with induction of p21(CIP1) and inhibition of expression of cyclin D1","volume":"62","author":"Suzui","year":"2002","journal-title":"Cancer Res.,"},{"key":"2022042513024884400_CIT0019","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1158\/1535-7163.309.3.3","article-title":"Acyclic retinoid activates retinoic acid receptor beta and induces transcriptional activation of p21(CIP1) in HepG2 human hepatoma cells","volume":"3","author":"Suzui","year":"2004","journal-title":"Mol. 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Ther.,"},{"key":"2022042513024884400_CIT0048","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.molcel.2004.08.010","article-title":"Mechanism of phosphorylation-dependent binding of APC to beta-catenin and its role in beta-catenin degradation","volume":"15","author":"Ha","year":"2004","journal-title":"Mol. Cell,"},{"key":"2022042513024884400_CIT0049","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S1097-2765(01)00241-6","article-title":"Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein","volume":"7","author":"Liu","year":"2001","journal-title":"Mol. Cell,"},{"key":"2022042513024884400_CIT0050","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1101\/gad.14.15.1837","article-title":"Wnt signaling and cancer","volume":"14","author":"Polakis","year":"2000","journal-title":"Genes Dev.,"}],"container-title":["Carcinogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/carcin\/advance-article-pdf\/doi\/10.1093\/carcin\/bgab099\/41135020\/bgab099.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/43\/3\/254\/43447881\/bgab099.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/carcin\/article-pdf\/43\/3\/254\/43447881\/bgab099.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T15:18:36Z","timestamp":1673536716000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/carcin\/article\/43\/3\/254\/6404558"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,20]]},"references-count":50,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,10,20]]},"published-print":{"date-parts":[[2022,4,25]]}},"URL":"https:\/\/doi.org\/10.1093\/carcin\/bgab099","relation":{},"ISSN":["0143-3334","1460-2180"],"issn-type":[{"value":"0143-3334","type":"print"},{"value":"1460-2180","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,3,1]]},"published":{"date-parts":[[2021,10,20]]}}}