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Cited by 62Hepatocellular Carcinoma Treatment and PrognosisLiver physiology and pathologyCancer, Lipids, and Metabolism

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

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Kowalik, Marta Anna, Puliga, Elisabetta, Cabras, Lavinia, Sulas, Pia, Petrelli, Annalisa, Perra, Andrea, Ledda-Columbano, Giovanna Maria, Morandi, Andrea +12 more·2020·Journal of Hepatology
DOI 10.1016/j.jhep.2019.12.018
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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.

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  • Overexpression or activation of several Hep-IDCONNECT transcription factors, GATA6, KLF9, TBX3, NR1H3, and THRB, has been shown to suppress hepatocarcinogenesis.

    “overexpression or activation of several Hep‐IDCONNECT TFs, GATA‐binding protein 6 (GATA6), krüppel‐like factor 9 (KLF9), T‐box transcription factor 3 (TBX3) and the nuclear receptors liver X receptor alpha (NR1H3 also known as LXR alpha) and thyroid hormone receptor beta (THRB), has been shown to suppress hepatocarcinogenesis (Fig 4C; Sun et al, 2014; Tan et al, 2019; Kowalik et al, 2020; Lin et a”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Kowalik et al, 2020

    The Discussion (page unavailable) supports an antitumor role for the THRB/KLF9 axis: T3 impaired HCC-cell growth, and KLF9 silencing partially reversed that effect. The cited paper does not establish suppression of hepatocarcinogenesis by GATA6, TBX3, or NR1H3, which are also included in the citing sentence. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • In a rat model of hepatocarcinogenesis, T3 was able to counteract the cancer-driven loss of expression of Hep-ID transcription factors.

    “interrogating the transcriptomic data obtained in a rat model of hepatocarcinogenesis (Kowalik et al, 2020) revealed that T3 was able to counteract the cancer‐driven loss of expression of Hep‐ID TFs (Fig 4J).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Kowalik et al, 2020

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Authors
Kowalik, M. A., Puliga, E., Cabras, L., Sulas, P., Petrelli, A., Perra, A., Ledda-Columbano, G. M., Morandi, A., Merlin, S., Orrù, C., Sanchez-Martin, C., Fornari, F., Gramantieri, L., Parri, M., Rasola, A., Bellomo, S. E., Sebastian, C., Follenzi, A., Giordano, S., & Columbano, A.
Affiliations
  • University of Cagliari (IT)
  • Candiolo Cancer Institute (IT)
  • University of Florence (IT)
  • Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
  • University of Padua (IT)
Corresponding author
  • Giordano, Silvia
  • Columbano, Amedeo
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2020-06
Volume
72
Issue
6
Pages
1159-1169
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2019.12.018
OpenAlex
W3000556507
Cited by
62
References
1
Citations by year
2026: 3 · 2025: 12 · 2024: 7 · 2023: 10 · 2022: 13 · 2021: 10 · 2020: 7
FWCI
5.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc-nd)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Padua Research Archive (University of Padova) (submittedVersion, other-oa)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
  • Florence Research (University of Florence) (submittedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion, other-oa)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by-nc-nd)
Funders
  • Fondazione di Sardegna
  • Associazione Italiana per la Ricerca sul Cancro
  • Ente Cassa di Risparmio di Firenze
Topics
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
hepatocellular carcinoma, triiodothyronine, thyroid hormones, thyroid hormone receptor beta, tumor differentiation, metabolic reprogramming, oxidative phosphorylation, Warburg effect, KLF9, hypothyroidism, hepatocarcinogenesis, thyromimetics
MeSH terms
Aged, Animals, Cell Differentiation, Disease Models, Animal, Female, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Mice, Nude, Middle Aged, Rats, Inbred F344, Triiodothyronine, Anticarcinogenic Agents, Rats, Wistar, Disease Progression, Gene Expression Profiling, Thyroid Hormone Receptors beta, Mice, Rats, Hep G2 Cells, Transcriptome, Carcinogenesis

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