Marta Anna Kowalik1, Elisabetta Puliga2, Lavinia Cabras1, Pia Sulas1, Annalisa Petrelli3, Andrea Perra1, Giovanna Maria Ledda-Columbano1, Andrea Morandi4, Simone Merlin5, Claudia Orrù2, Carlos Sanchez-Martin6, Francesca Fornari7, Laura Gramantieri7, Matteo Parri4, Andrea Rasola6, Sara Erika Bellomo3, Carlos Sebastian3, Antonia Follenzi5, Silvia Giordano8, Amedeo Columbano9. 1. Department of Biomedical Sciences, School of Medicine, University of Cagliari, Italy. 2. Department of Biomedical Sciences, School of Medicine, University of Cagliari, Italy; Department of Oncology, University of Turin, Italy; Present address: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy. 3. Candiolo Cancer Institute -FPO, IRCCS, Candiolo, Italy. 4. Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy. 5. Department of Health Sciences, University of Piemonte Orientale, Novara, Italy. 6. Department of Biomedical Sciences, University of Padova, Italy. 7. CRBA Azienda Ospedaliero-Universitaria Policlinico S. Orsola Malpighi, 40138, Bologna, Italy. 8. Candiolo Cancer Institute -FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Turin, Italy. Electronic address: silvia.giordano@unito.it. 9. Department of Biomedical Sciences, School of Medicine, University of Cagliari, Italy. Electronic address: columbano@unica.it.
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.
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 humanHCC 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: Linda Skibsted Kornerup; Frederik Kraglund; Ulla Feldt-Rasmussen; Peter Jepsen; Hendrik Vilstrup Journal: Gastrointest Tumors Date: 2021-11-04
Authors: Nicole Lafontaine; Purdey J Campbell; Juan E Castillo-Fernandez; Shelby Mullin; Ee Mun Lim; Phillip Kendrew; Michelle Lewer; Suzanne J Brown; Rae-Chi Huang; Phillip E Melton; Trevor A Mori; Lawrence J Beilin; Frank Dudbridge; Tim D Spector; Margaret J Wright; Nicholas G Martin; Allan F McRae; Vijay Panicker; Gu Zhu; John P Walsh; Jordana T Bell; Scott G Wilson Journal: J Clin Endocrinol Metab Date: 2021-04-23 Impact factor: 5.958