Thyroid hormone receptor ligands induce regression of rat preneoplastic liver lesions causing their reversion to a differentiated phenotype

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‐β 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/cm2) 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/cm2). A reduction of GSTP‐positive foci was also observed in rats fed a CD + GC‐1 diet (28/cm2 versus 75/cm2 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. Conclusion: 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.)