{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:27:25Z","timestamp":1762100845317,"version":"3.30.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2344,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,4]]},"abstract":"<jats:sec>\n            <jats:title>Abstract<\/jats:title>\n            <jats:p>Triiodothyronine (T3), through interaction with its intracellular thyroid hormone receptors (TRs), influences various physiological functions, including metabolism, development, and growth. We investigated the effect of T3 and the selective TR-\u03b2 agonist GC-1 in two models of hepatocarcinogenesis. Preneoplastic lesions were induced in F-344 rats via a single dose of diethylnitrosamine, followed by a choline-deficient (CD) diet for 10 weeks. Rat subgroups were then fed the CD diet or a CD diet containing either 4 mg\/kg T3 or 5 mg\/kg GC-1 for another week. Rats fed a CD diet alone showed a large number (65\/cm<jats:sup>2<\/jats:sup>) of preneoplastic lesions positive for the placental form of glutathione <jats:italic toggle=\"yes\">S<\/jats:italic>-transferase (GSTP). Coadministration of T3 for the last week caused an almost complete disappearance of the foci (3\/cm<jats:sup>2<\/jats:sup>). A reduction of GSTP-positive foci was also observed in rats fed a CD + GC-1 diet (28\/cm<jats:sup>2<\/jats:sup> versus 75\/cm<jats:sup>2<\/jats:sup> of rats fed a CD diet alone) in the absence of significant differences in labeling or apoptotic index of preneoplastic hepatocytes between the two groups. An antitumoral effect of GC-1 was also observed with the resistant hepatocyte model of hepatocarcinogenesis. Nodule regression was associated with a return to a fully differentiated phenotype, indicated by the loss of the fetal markers GSTP and gamma glutamyl transpeptidase, and reacquisition of the activity of glucose 6-phosphatase and adenosine triphosphatase, two enzymes expressed in normal hepatocytes. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Our results indicate that activated TRs negatively influence the carcinogenic process through induction of a differentiation program of preneoplastic hepatocytes. The results also suggest that TRs could be a meaningful target in liver cancer therapy. (Hepatology 2009.)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.22750","type":"journal-article","created":{"date-parts":[[2008,11,19]],"date-time":"2008-11-19T15:10:18Z","timestamp":1227107418000},"page":"1287-1296","update-policy":"http:\/\/dx.doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":58,"title":["Thyroid hormone receptor ligands induce regression of rat preneoplastic liver lesions causing their reversion to a differentiated phenotype #"],"prefix":"10.1097","volume":"49","author":[{"given":"Andrea","family":"Perra","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta Anna","family":"Kowalik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Pibiri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna M.","family":"Ledda-Columbano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amedeo","family":"Columbano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"R1-26-20241201","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/jcp.21172","article-title":"Liver regeneration.","volume":"213","author":"Michalopoulos","year":"2007","journal-title":"J Cell Physiol"},{"key":"R2-26-20241201","first-page":"201","article-title":"Cell proliferation and experimental liver cancer. In: Cameron HN, Linsell DA, Warwick GP, eds. Liver Cell Cancer.","volume":"153-","author":"Craddock","year":"1976","journal-title":"Amsterdam: ElsevierNorth Holland Biochemical Press"},{"key":"R3-26-20241201","first-page":"7415","article-title":"Increased cell division as a cause of human cancer.","volume":"50","author":"PrestonMartin","year":"1990","journal-title":"Cancer Res"},{"key":"R5-26-20241201","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/hep.510240341","article-title":"An update on iron metabolism: summary of the Fifth International Conference on Disorders of Iron Metabolism.","volume":"24","author":"Bonkovsky","year":"1996","journal-title":"HEPATOLOGY"},{"key":"R6-26-20241201","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/S1089-3261(05)70107-0","article-title":"Hepatocellular cancer. A century of progress.","volume":"4","author":"Kew","year":"2000","journal-title":"Clin liver Dis"},{"key":"R7-26-20241201","first-page":"3471","article-title":"p53 mutations, chronic hepatitis B virus infection, and aflotoxin exposure in hapatocellular carcinoma in Taiwan.","volume":"15","author":"Lunn","year":"1997","journal-title":"Cancer Res"},{"key":"R8-26-20241201","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1126\/science.2136249","article-title":"Too many rodent carcinogens: mitogenesis increases mutagenesis.","volume":"249","author":"Ames","year":"1990","journal-title":"Science"},{"key":"R9-26-20241201","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1126\/science.1989073","article-title":"Mitogenesis is only one factor in carcinogenesis.","volume":"5","author":"Weinstein","year":"1991","journal-title":"Science"},{"key":"R10-26-20241201","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/hep.1840200521","article-title":"Hepatocyte proliferation and gene expression induced by triiodothyronine in vivo and in vitro.","volume":"20","author":"Francavilla","year":"1994","journal-title":"HEPATOLOGY"},{"key":"R11-26-20241201","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1096\/fj.00-0416com","article-title":"Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3).","volume":"15","author":"Pibiri","year":"2001","journal-title":"FASEB J"},{"key":"R12-26-20241201","first-page":"603","article-title":"Cell proliferation induced by triiodothyronine in rat liver is associated with nodule regression and reduction of hepatocellular carcinomas.","volume":"60","author":"LeddaColumbano","year":"2000","journal-title":"Cancer Res"},{"key":"R13-26-20241201","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1080\/01926230390173851","article-title":"Different effects of the liver mitogens triiodothyronine and ciprofibrate on the development of rat hepatocellular carcinoma.","volume":"31","author":"LeddaColumbano","year":"2003","journal-title":"Toxicol Pathol"},{"key":"R15-26-20241201","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1002\/ijc.2910290414","article-title":"Progression of carcinogeninduced foci of gammaglutamyltranspeptidasepositive hepatocytes to hepatoma in rats fed a cholinedeficient diet.","volume":"29","author":"Takahashi","year":"1982","journal-title":"Int J Cancer"},{"key":"R16-26-20241201","first-page":"852","article-title":"Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation.","volume":"GI290","author":"Reddy","year":"2005","journal-title":"Am J Physiol Gastrointestinal Liver Physiol"},{"key":"R17-26-20241201","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1056\/NEJM200102153440707","article-title":"Thyroid hormone and the cardiovascular system.","volume":"344","author":"Klein","year":"2001","journal-title":"N Engl J Med"},{"key":"R18-26-20241201","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/S1074-5521(98)90168-5","article-title":"A high affinity subtypeselective agonist ligand for the thyroid hormone receptor.","volume":"5","author":"Chiellini","year":"1998","journal-title":"Chem Biol"},{"key":"R19-26-20241201","first-page":"1092","article-title":"Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline deficient diet.","volume":"38","author":"Shinozuka","year":"1978","journal-title":"Cancer Res"},{"key":"R20-26-20241201","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/263701a0","article-title":"New principle for the analysis of chemical carcinogenesis.","volume":"263","author":"Solt","year":"1976","journal-title":"Nature"},{"key":"R21-26-20241201","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1177\/17.8.517","article-title":"Histochemical and ultrastructural demonstration of gammaglutamyl transpeptidase activity.","volume":"17","author":"Rutenburg","year":"1969","journal-title":"J Histochem Cytochem"},{"key":"R22-26-20241201","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/ajcp\/27.1.13","article-title":"Histochemistry of hepatic phosphatase at a physiological PH.","volume":"27","author":"Wachstein","year":"1957","journal-title":"Am J Clin Pathol"},{"key":"R23-26-20241201","first-page":"36","article-title":"Image processing with ImageJ.","volume":"11","author":"Abramoff","year":"2004","journal-title":"Biophotonics International"},{"key":"R24-26-20241201","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1096\/fj.08-108464","article-title":"Thyroid hormone (T3) and Tr agonist GC1 inhibitreverse nonalcoholic fatty liver in rats.","volume":"22","author":"Perra","year":"2008","journal-title":"FASEB J"},{"key":"R25-26-20241201","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1289\/ehp.9193181","article-title":"Biochemical markers associated with the stages of promotion and progression during hepatocarcinogenesis in the rat.","volume":"93","author":"Pitot","year":"1991","journal-title":"Environ Health Persp"},{"key":"R26-26-20241201","first-page":"564","article-title":"A common biochemical pattern in preneoplastic hepatocyte nodules generated in four different models in the rat.","volume":"45","author":"Roomi","year":"1985","journal-title":"Cancer Res"},{"key":"R27-26-20241201","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.1073\/pnas.82.12.3964","article-title":"Purification, induction, and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis.","volume":"82","author":"Satoh","year":"1985","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R28-26-20241201","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/carcin\/9.4.547","article-title":"Effect of modifying agents on the phenotypic expression of cytochrome P450, glutathione Stransferase molecular forms, microsomal epoxide hydrolase, glucose6phosphate dehydrogenase and gammaglutamyltranspeptidase in rat liver preneoplastic lesions.","volume":"9","author":"Tsuda","year":"1988","journal-title":"Carcinogenesis"},{"key":"R29-26-20241201","first-page":"2330","article-title":"Kinetics of phenotypic maturation of remodeling of hyperplastic nodules during liver carcinogenesis.","volume":"42","author":"Enomoto","year":"1982","journal-title":"Cancer Res"},{"key":"R30-26-20241201","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/carcin\/4.5.595","article-title":"Phenotypic instability in focal and nodular lesions induced in a short term system in the rat liver.","volume":"4","author":"Moore","year":"1983","journal-title":"Carcinogenesis"},{"key":"R31-26-20241201","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1093\/carcin\/16.6.1271","article-title":"Inhibition of apoptosis during 2,3,7,8tetrachloropdioxinmediated tumour promotion in rat liver.","volume":"16","author":"Stinchcombe","year":"1995","journal-title":"Carcinogenesis"},{"key":"R32-26-20241201","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1093\/carcin\/5.4.453","article-title":"Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters.","volume":"5","author":"Bursch","year":"1984","journal-title":"Carcinogenesis"},{"key":"R33-26-20241201","first-page":"1850","article-title":"Inhibition of promotion and persistent nodule growth by SadenosylLmethionine in rat liver carcinogenesis: role of remodeling and apoptosis.","volume":"49","author":"Garcea","year":"1989","journal-title":"Cancer Res"},{"key":"R34-26-20241201","doi-asserted-by":"crossref","first-page":"9995","DOI":"10.1073\/pnas.91.21.9995","article-title":"Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver.","volume":"91","author":"GrauslKraupp","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R35-26-20241201","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1289\/ehp.9193205","article-title":"An overview of peroxisome proliferatorinduced hepatocarcinogenesis.","volume":"93","author":"Rao","year":"1991","journal-title":"Environ Health Perspect"},{"key":"R36-26-20241201","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1152\/physrev.2001.81.3.1097","article-title":"Physiological and molecular basis of thyroid hormone action.","volume":"81","author":"Yen","year":"2001","journal-title":"Physiol Rev"},{"key":"R37-26-20241201","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1056\/NEJM199409293311306","article-title":"The molecular basis of thyroid hormone action.","volume":"331","author":"Brent","year":"1994","journal-title":"New Engl J Med"},{"key":"R39-26-20241201","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1096\/fasebj.5.14.1661245","article-title":"Retinoid and their receptors in differentiation, embryogenesis, and neoplasia.","volume":"5","author":"De Luca","year":"1991","journal-title":"FASEB J"},{"key":"R40-26-20241201","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1096\/fasebj.10.10.8751714","article-title":"Liver regeneration versus direct hyperplasia.","volume":"10","author":"Columbano","year":"1996","journal-title":"FASEB J"},{"key":"R41-26-20241201","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1093\/carcin\/bgh221","article-title":"Induction of hepatocyte proliferation by retinoic acid.","volume":"25","author":"LeddaColumbano","year":"2004","journal-title":"Carcinogenesis"},{"key":"R42-26-20241201","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/sj.onc.1202018","article-title":"In vivo hepatocyte proliferation is inducible through a TNF and IL6independent pathway.","volume":"17","author":"LeddaColumbano","year":"1998","journal-title":"Oncogene"},{"key":"R43-26-20241201","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1385\/CBB:32:1-3:187","article-title":"Peroxisome proliferatoractivated receptors, coactivators, and downstream targets.","volume":"32","author":"Qi","year":"2000","journal-title":"Cell Biochem Biophys"},{"key":"R44-26-20241201","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1038\/ng.2007.15","article-title":"Loss of Trim24 (Tif1a) gene function confers oncogenic activity to retinoic acid receptor alpha.","volume":"39","author":"Khetchoumian","year":"2007","journal-title":"Nat Genetics"},{"key":"R45-26-20241201","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/toxsci\/kfi044","article-title":"Effects in the early and late phase of treatment with KAT681, a liver selective thyromimetic, on rat hepatocarcinogenesis induced by 2acetylaminofluorene and partial hepatectomy after diethylnitrosamine initiation.","volume":"84","author":"Hayashi","year":"2005","journal-title":"Toxicol Sci"},{"key":"R46-26-20241201","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1210\/endo.142.2.7927","article-title":"Impaired interaction of mutant thyroid hormone receptors associated with human hepatocellular carcinoma with transcriptional coregulators.","volume":"142","author":"Lin","year":"2001","journal-title":"Endocrinology"},{"key":"R47-26-20241201","doi-asserted-by":"crossref","first-page":"5308","DOI":"10.1210\/endo.138.12.5625","article-title":"Dominant negative activity of mutant thyroid hormone 1 receptors from patients with hepatocellular carcinoma.","volume":"138","author":"Lin","year":"1997","journal-title":"Endocrinology"},{"key":"R48-26-20241201","doi-asserted-by":"crossref","first-page":"4241","DOI":"10.1002\/j.1460-2075.1994.tb06744.x","article-title":"Thyroid abnormalities and hepatocellular carcinoma in mice transgenic for verbA.","volume":"13","author":"Barlow","year":"1994","journal-title":"EMBO J"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.22750","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200904000-00026","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T13:32:40Z","timestamp":1733059960000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200904000-00026"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,4]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2009]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.22750","relation":{},"ISSN":["0270-9139"],"issn-type":[{"type":"print","value":"0270-9139"}],"subject":[],"published":{"date-parts":[[2009,4]]}}}