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

Carla Frau, Roberto Loi, Annalisa Petrelli, Andrea Perra, Silvia Menegon, Marta Anna Kowalik, Silvia Pinna, Vera Piera Leoni, Francesca Fornari, Laura Gramantieri, Giovanna Maria Ledda-Columbano, Silvia Giordano, Amedeo Columbano

Research output: Contribution to journalArticle

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Abstract

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate most of the effects elicited by the thyroid hormone, 3,5,3′-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 TRβ1 and TRα1 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, TRβ1 and, to a lesser extent, TRα1 down-regulation was observed only in preneoplastic lesions positive for the progenitor cell marker, cytokeratin-19 (Krt-19) and characterized by a higher proliferative activity, compared to the Krt-19 negative ones. TRβ1 down-regulation was observed also in the vast majority of the analyzed human HCCs, compared to the matched peritumorous liver or to normal liver. Hyperthyroidism induced by T3 treatment caused up-regulation of TRβ1 and of its target genes in Krt-19+ preneoplastic rat lesions and was associated with nodule regression. In HCC, TRβ1 down-regulation was not the result of hypermethylation of its promoter, but was associated with an increased expression of TRβ1-targeting microRNAs ([miR]-27a, -181a, and -204). An inverse correlation between TRβ1 and miR-181a was also found in human cirrhotic peritumoral tissue, compared to normal liver. Conclusion: Down-regulation of TRs, especially TRβ1, is an early and relevant event in liver cancer development and is species and etiology independent. 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.

Original languageEnglish
Pages (from-to)249-259
Number of pages11
JournalHepatology
Volume61
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

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Hypothyroidism
Hepatocellular Carcinoma
Down-Regulation
Thyroid Hormone Receptors
MicroRNAs
Liver
Carcinogenesis
Keratin-19
Triiodothyronine
Hyperthyroidism
Liver Neoplasms
Thyroid Hormones
Oncogenes
Genes
Hepatocytes
Neoplasms
Transcription Factors
Up-Regulation
Stem Cells
Ligands

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Frau, C., Loi, R., Petrelli, A., Perra, A., Menegon, S., Kowalik, M. A., ... Columbano, A. (2015). Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats. Hepatology, 61(1), 249-259. https://doi.org/10.1002/hep.27399

Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats. / Frau, Carla; Loi, Roberto; Petrelli, Annalisa; Perra, Andrea; Menegon, Silvia; Kowalik, Marta Anna; Pinna, Silvia; Leoni, Vera Piera; Fornari, Francesca; Gramantieri, Laura; Ledda-Columbano, Giovanna Maria; Giordano, Silvia; Columbano, Amedeo.

In: Hepatology, Vol. 61, No. 1, 01.01.2015, p. 249-259.

Research output: Contribution to journalArticle

Frau, C, Loi, R, Petrelli, A, Perra, A, Menegon, S, Kowalik, MA, Pinna, S, Leoni, VP, Fornari, F, Gramantieri, L, Ledda-Columbano, GM, Giordano, S & Columbano, A 2015, 'Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats', Hepatology, vol. 61, no. 1, pp. 249-259. https://doi.org/10.1002/hep.27399
Frau, Carla ; Loi, Roberto ; Petrelli, Annalisa ; Perra, Andrea ; Menegon, Silvia ; Kowalik, Marta Anna ; Pinna, Silvia ; Leoni, Vera Piera ; Fornari, Francesca ; Gramantieri, Laura ; Ledda-Columbano, Giovanna Maria ; Giordano, Silvia ; Columbano, Amedeo. / Local hypothyroidism favors the progression of preneoplastic lesions to hepatocellular carcinoma in rats. In: Hepatology. 2015 ; Vol. 61, No. 1. pp. 249-259.
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abstract = "Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate most of the effects elicited by the thyroid hormone, 3,5,3′-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 TRβ1 and TRα1 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, TRβ1 and, to a lesser extent, TRα1 down-regulation was observed only in preneoplastic lesions positive for the progenitor cell marker, cytokeratin-19 (Krt-19) and characterized by a higher proliferative activity, compared to the Krt-19 negative ones. TRβ1 down-regulation was observed also in the vast majority of the analyzed human HCCs, compared to the matched peritumorous liver or to normal liver. Hyperthyroidism induced by T3 treatment caused up-regulation of TRβ1 and of its target genes in Krt-19+ preneoplastic rat lesions and was associated with nodule regression. In HCC, TRβ1 down-regulation was not the result of hypermethylation of its promoter, but was associated with an increased expression of TRβ1-targeting microRNAs ([miR]-27a, -181a, and -204). An inverse correlation between TRβ1 and miR-181a was also found in human cirrhotic peritumoral tissue, compared to normal liver. Conclusion: Down-regulation of TRs, especially TRβ1, is an early and relevant event in liver cancer development and is species and etiology independent. 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.",
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AU - Menegon, Silvia

AU - Kowalik, Marta Anna

AU - Pinna, Silvia

AU - Leoni, Vera Piera

AU - Fornari, Francesca

AU - Gramantieri, Laura

AU - Ledda-Columbano, Giovanna Maria

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AU - Columbano, Amedeo

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