Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming.
Aged
Animals
Anticarcinogenic Agents
/ administration & dosage
Carcinogenesis
/ drug effects
Carcinoma, Hepatocellular
/ drug therapy
Cell Differentiation
/ drug effects
Disease Models, Animal
Disease Progression
Female
Gene Expression Profiling
Hep G2 Cells
Humans
Liver Neoplasms
/ drug therapy
Male
Mice
Mice, Nude
Middle Aged
Rats
Rats, Inbred F344
Rats, Wistar
Thyroid Hormone Receptors beta
/ metabolism
Transcriptome
Triiodothyronine
/ administration & dosage
Differentiation
HCC
KLF9
Metabolic reprogramming
OXPHOS
PPP
Rats
T3
Thyroid hormone receptors
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
14
05
2019
revised:
18
12
2019
accepted:
20
12
2019
pubmed:
19
1
2020
medline:
9
11
2021
entrez:
19
1
2020
Statut:
ppublish
Résumé
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. 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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31954205
pii: S0168-8278(20)30009-X
doi: 10.1016/j.jhep.2019.12.018
pii:
doi:
Substances chimiques
Anticarcinogenic Agents
0
Thyroid Hormone Receptors beta
0
Triiodothyronine
06LU7C9H1V
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1159-1169Informations de copyright
Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest concerning this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details.