Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats

Frau C;LOI, ROBERTO;Petrelli A;PERRA, ANDREA;Menegon S;KOWALIK, MARTA ANNA;Pinna S;LEONI, VERA PIERA;Fornari F;Gramantieri L;LEDDA, GIOVANNA MARIA;Giordano S;COLUMBANO, AMEDEO

2015-01-01

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Abstract

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that medi- ate most of the effects elicited by the thyroid hormone, 3,5,30-L-triiodothyronine (T3). TRs have been implicated in tumorigenesis, although it is unclear whether they act as oncogenes or tumor suppressors, and at which stage of tumorigenesis their dysregulation occurs. Using the resistant-hepatocyte rat model (R-H model), we found down- regulation of TRb1 and TRa1 and their target genes in early preneoplastic lesions and hepatocellular carcinoma (HCCs), suggesting that a hypothyroid status favors the onset and progression of preneoplastic lesions to HCC. Notably, TRb1 and, to a lesser extent, TRa1 down-regulation was observed only in preneoplastic lesions positive for the pro- genitor cell marker, cytokeratin-19 (Krt-19) and characterized by a higher proliferative activity, compared to the Krt-19 negative ones. TRb1 down-regulation was observed also in the vast majority of the analyzed human HCCs, compared to the matched peri- tumorous liver or to normal liver. Hyperthyroidism induced by T3 treatment caused up-regulation of TRb1 and of its target genes in Krt-191 preneoplastic rat lesions and was associated with nodule regression. In HCC, TRb1 down-regulation was not the result of hypermethylation of its promoter, but was associated with an increased expres- sion of TRb1-targeting microRNAs ([miR]-27a, -181a, and -204). An inverse correlation between TRb1 and miR-181a was also found in human cirrhotic peritumoral tissue, compared to normal liver. Conclusion: Down-regulation of TRs, especially TRb1, is an early and relevant event in liver cancer development and is species and etiology inde- pendent. The results also suggest that a hypothyroid status of preneoplastic lesions may contribute to their progression to HCC and that the reversion of this condition may represent a possible therapeutic goal to interfere with the development of this tumor.