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Here, we investigated the relationship between LDLRAD4 downregulation and TGF\u03b2 signaling in nongenotoxic hepatocarcinogenesis. The transcripts of <jats:italic>Tgfb<\/jats:italic> and <jats:italic>Hb\u2010egf<\/jats:italic> increased after \u226528 days of treatment. After 84 or 90 days, <jats:italic>Snai1<\/jats:italic> increased transcripts and the subpopulation of GST\u2010P<jats:sup>+<\/jats:sup> foci downregulating LDLRAD4 co\u2010expressed TGF\u03b21, phosphorylated EGFR, or phosphorylated AKT2, and downregulated PTEN, showing higher incidences than those in GST\u2010P<jats:sup>+<\/jats:sup> foci expressing LDLRAD4. The subpopulation of GST\u2010P<jats:sup>+<\/jats:sup> foci downregulating LDLRAD4 also co\u2010expressed caveolin\u20101 or TACE\/ADAM17, suggesting that disruptive activation of TGF\u03b2 signaling through a loss of LDLRAD4 enhances EGFR and PTEN\/AKT\u2010dependent pathways via caveolin\u20101\u2010dependent activation of TACE\/ADAM17 during nongenotoxic hepatocarcinogenesis. The numbers of c\u2010MYC<jats:sup>+<\/jats:sup> cells and PCNA<jats:sup>+<\/jats:sup> cells were higher in LDLRAD4\u2010downregulated GST\u2010P<jats:sup>+<\/jats:sup> foci than in LDLRAD4\u2010expressing GST\u2010P<jats:sup>+<\/jats:sup> foci, suggesting a preferential proliferation of pre\u2010neoplastic cells by LDLRAD4 downregulation. Nongenotoxic hepatocarcinogens markedly downregulated <jats:italic>Nox4<\/jats:italic> after 28 days and later decreased cleaved caspase 3<jats:sup>+<\/jats:sup> cells in LDLRAD4\u2010downregulated GST\u2010P<jats:sup>+<\/jats:sup> foci, suggesting an attenuation of apoptosis by LDLRAD4 downregulation through activation of the EGFR pathway. At the late hepatocarcinogenesis stage in a two\u2010stage model, LDLRAD4 downregulation was higher in adenoma and carcinoma than in pre\u2010neoplastic cell foci, suggesting a role of LDLRAD4 downregulation in tumor development. Our results suggest that nongenotoxic hepatocarcinogens cause disruptive activation of TGF\u03b2 signaling through downregulating LDLRAD4 toward carcinogenesis in the rat liver.<\/jats:p>","DOI":"10.1002\/jat.3998","type":"journal-article","created":{"date-parts":[[2020,6,29]],"date-time":"2020-06-29T00:04:57Z","timestamp":1593389097000},"page":"1467-1479","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Downregulation of low\u2010density lipoprotein receptor class A domain\u2010containing protein 4 (<i>Ldlrad4<\/i>) in the liver of rats treated with nongenotoxic hepatocarcinogen to induce transforming growth factor \u03b2 signaling promoting cell proliferation and suppressing apoptosis in early hepatocarcinogenesis"],"prefix":"10.1002","volume":"40","author":[{"given":"Yuko","family":"Ito","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences Gifu University  Gifu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences Gifu University  Gifu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Masubuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences Gifu University  Gifu Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satomi","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Cooperative Division of Veterinary Sciences, Graduate School of Agriculture Tokyo University of Agriculture and Technology  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromu","family":"Okano","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Cooperative Division of Veterinary Sciences, Graduate School of Agriculture Tokyo University of Agriculture and Technology  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiyo","family":"Saito","sequence":"additional","affiliation":[{"name":"Chemicals Evaluation and Research Institute  Tokyo Japan"},{"name":"Department of Toxicology, Faculty of Veterinary Medicine Okayama University of Science  Ehime Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Akahori","sequence":"additional","affiliation":[{"name":"Chemicals Evaluation and Research Institute  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilan","family":"Jin","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology, College of Animal Science and Technology Veterinary Medicine Southwest University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinori","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Cooperative Division of Veterinary Sciences, Graduate School of Agriculture Tokyo University of Agriculture and Technology  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3417-9697","authenticated-orcid":false,"given":"Makoto","family":"Shibutani","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Cooperative Division of Veterinary Sciences, Graduate School of Agriculture Tokyo University of Agriculture and Technology  Tokyo Japan"},{"name":"Institute of Global Innovation Research Tokyo University of Agriculture and Technology  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(81)90048-3"},{"key":"e_1_2_7_3_1","first-page":"553","article-title":"Thioacetamide hepatocarcinogenesis","volume":"71","author":"Becker F. 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