title: Thyroid hormone receptor ligands induce regression of rat preneoplastic liver lesions causing their reversion to a differentiated phenotype.
abstract: 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-beta 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(2)) of preneoplastic lesions positive for the placental form of glutathione S-transferase (GSTP). Coadministration of T3 for the last week caused an almost complete disappearance of the foci (3/cm(2)). A reduction of GSTP-positive foci was also observed in rats fed a CD + GC-1 diet (28/cm(2) versus 75/cm(2) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Cagliari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Perra
authors.forename: Marta Anna
authors.initials: MA
authors.lastname: Kowalik
authors.forename: Monica
authors.initials: M
authors.lastname: Pibiri
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002796:Choline Deficiency / Q000150:complications; D004052:Diethylnitrosamine; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D008297:Male; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D011916:Rats, Inbred F344; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D014284:Triiodothyronine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D004052:Diethylnitrosamine; D005982:Glutathione Transferase