Preneoplastic hepatocyte hypothyroidism underlies hepatocellular carcinoma progression

Thyroid hormones elicit many cellular and metabolic effects. Most of them are mediated by the thyroid hormone 3,5,3'-L-triiodothyronine (T3) nuclear receptors (THRs), which act as transcription factors. THRs have also been implicated in tumorigenesis, although it is unclear whether they act as oncogenes or tumor suppressors. Here, experiments were performed to determine the role of THRs in hepatocellular carcinoma development. Using the Resistant-Hepatocyte model (RH model) of rat hepatocarcinigenesis, we found downregulation of THR?1 and THR?1 in most of early preneoplastic lesions and of HCCs. THR?1 and, to a lesser extent, THR?1 downregulation was observed only in preneoplastic lesions positive for the progenitor cell marker cytokeratin-19 (KRT-19), which are characterized by a higher proliferative activity compared to KRT-19 negative ones. Accordingly, THRs target genes were strongly down-regulated in KRT-19+ lesions. In rat HCC THR?1 decrease was not due to hypermethylation of the THR?1 promoter but was associated with an increased expression of miR-27a, -181a and -204, known to target this receptor in other cell types. Accordingly, transfection of hepatoma cell lines with these miRNAs led to down-regulation of THR?1. Downregulation of THR?1 expression was observed also in the vast majority of the analyzed human HCCs compared to peritumorous liver of the same patients or to normal liver. These results show that downregulation of THRs, especially THR?1, is an early and relevant event in liver cancer development, species- and etiology-independent. They also suggest that a hypothyroid status of preneoplastic lesions may contribute to their progression to HCC.