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 THRβ1 and THRα1 in most of early preneoplastic lesions and of HCCs. THRβ1 and, to a lesser extent, THRα1 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 THRβ1 decrease was not due to hypermethylation of the THRβ1 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 THRβ1. Downregulation of THRβ1 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 THRβ1, 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.