Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming.

Abstract

BACKGROUND & AIMS:

Only limited therapeutic options are currently available for hepatocellular carcinoma (HCC), making the development of effective alternatives essential. Based on the recent finding that systemic or local hypothyroidism is associated with HCC development in humans and rodents, we investigated whether the thyroid hormone triiodothyronine (T3) could inhibit the progression of HCCs.

METHODS:

Different rat and mouse models of hepatocarcinogenesis were investigated. The effect of T3 on tumorigenesis and metabolism/differentiation was evaluated by transcriptomic analysis, quantitative reverse transcription PCR, immunohistochemistry, and enzymatic assay.

RESULTS:

A short treatment with T3 caused a shift in the global expression profile of the most aggressive preneoplastic nodules towards that of normal liver. This genomic reprogramming preceded the disappearance of nodules and involved reprogramming of metabolic genes, as well as pro-differentiating transcription factors, including Kruppel-like factor 9, a target of the thyroid hormone receptor β (TRβ). Treatment of HCC-bearing rats with T3 strongly reduced the number and burden of HCCs. Reactivation of a local T3/TRβ axis, a switch from Warburg to oxidative metabolism and loss of markers of poorly differentiated hepatocytes accompanied the reduced burden of HCC. This effect persisted 1 month after T3 withdrawal, suggesting a long-lasting effect of the hormone. The antitumorigenic effect of T3 was further supported by its inhibitory activity on cell growth and the tumorigenic ability of human HCC cell lines.

CONCLUSIONS:

Collectively, these findings suggest that reactivation of the T3/TRβ axis induces differentiation of neoplastic cells towards a more benign phenotype and that T3 or its analogs, particularly agonists of TRβ, could be useful tools in HCC therapy.

LAY SUMMARY:

Hepatocellular carcinoma (HCC) represents an important challenge for global health. Recent findings showed that systemic or local hypothyroidism is associated with HCC development. In rat models, we showed that administration of the thyroid hormone T3 impaired HCC progression, even when given at late stages. This is relevant from a translational point of view as HCC is often diagnosed at an advanced stage when it is no longer amenable to curative treatments. Thyroid hormones and/or thyromimetics could be useful for the treatment of patients with HCC.

• Authors: Marta Anna Kowalik, Elisabetta Puliga, Lavinia Cabras, Pia Sulas, Annalisa Petrelli, Andrea Perra, Giovanna Maria Ledda-Columbano, Andrea Morandi, Simone Merlin, Claudia Orrù, Carlos Sanchez-Martin, Francesca Fornari, Laura Gramantieri, Matteo Parri, Andrea Rasola, Sara Erika Bellomo, Carlos Sebastian, Antonia Follenzi, Silvia Giordano, Amedeo Columbano
• Journal: Journal of hepatology (J Hepatol) Vol. 72 Issue 6 Pg. 1159-1169 (06 2020) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 31954205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Thyroid Hormone Receptors beta
• Triiodothyronine

Topics

• Aged
• Animals
• Anticarcinogenic Agents (administration & dosage)
• Carcinogenesis (drug effects, metabolism)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Differentiation (drug effects)
• Disease Models, Animal
• Disease Progression
• Female
• Gene Expression Profiling
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Rats
• Rats, Inbred F344
• Rats, Wistar
• Thyroid Hormone Receptors beta (metabolism)
• Transcriptome
• Triiodothyronine (administration & dosage, metabolism)