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

Abstract

The T3/TRb axis is altered in human HCC. T3 induces a rapid differentiation program in hepatic preneoplastic lesions. Repeated cycles of T3 impair HCC progression. The antitumorigenic effect of T3 is long-lasting and is maintained after withdrawal. T3 reverts the metabolic profile of HCC to that of a normal hepatocyte.

Animal Models: A Useful Tool to Unveil Metabolic Changes in Hepatocellular Carcinoma

“…It has been observed that a 7-day treatment with T3 of rats bearing hepatic preneoplastic nodules characterized by local hypothyroidism [ 180 ] and Warburg phenotype [ 54 ], induced their rapid regression [ 181 ]. T3 administration severely affected the expression of metabolic genes, and particularly, those involved in the PPP and mitochondrial respiration, as early as two days after treatment [ 145 ]. Even more striking was the fact that T3 administration to HCC bearing rats induced tumor regression by prompting a metabolic reprogramming [ 145 ].…”

“…In addition, genetic inactivation of Nrf2 in rats [ 124 ] fully prevented the formation of preneoplastic foci in rats treated with DENA and CMD diet and was associated with the absent/low expression of Nrf2 target genes, such as Gstp1 and G6pd [ 84 ]. The fact that Nrf2 plays a crucial role in HCC development by inducing metabolic reprogramming was recently supported by the finding that inhibition of the Keap1-Nrf2 pathway by thyroid hormone (T3) is associated with a switch from Warburg metabolism to OXPHOS which precedes regression of rat HCCs [ 145 ] (for a detailed description of the effect of T3, see chapter 7 entitled Pharmacological targeting of Warburg metabolism in HCC). The discovery of specific Nrf2 inhibitors, unfortunately lacking at present, will help to better elucidate the role of this transcription factor in HCC development and, hopefully, to efficiently impair the Nrf2-dependent metabolic reprogramming of neoplastic hepatocytes.…”

“…The importance of rewiring of cellular metabolism from enhanced glycolytic phenotype towards OXPHOS has been recently reported by Kowalik et al [ 145 ]. Encouraging results have been observed in the RH model following treatment with thyroid hormone 3,5,3′-triiodo-L-thyronine (T3).…”

Thyroid hormones in diabetes, cancer, and aging

“…In the late nineteenth century, Beatson proposed the use of thyroid extract in conjunction with oophorectomy as a therapy for breast cancer (Beatson, 1896). In this line, TH treatment has been shown to reduce HCC progression, development of lung metastases, and the risk of colorectal cancer (Frau et al, 2015; Kowalik et al, 2020; Ledda‐Columbano et al, 2000; Rennert et al, 2010). Despite the fact that THs are known to induce hepatocyte proliferation, TH administration or treatments with the THRβ agonist sobetirome induces regression of carcinogen‐induced hepatic nodules in xenobiotic‐based research models (Perra et al, 2009).…”

Kommentar

“…Der antisteatotische Effekt von Resmetirom scheint gegenüber Agonisten anderer nukleärer Hormonrezeptoren (FXR, PPAR) ausgeprägter. Vor dem Hintergrund eines hohen Risikos der Entstehung hepatozellulärer Karzinome bereits im präzirrhotischen Stadium sind auch die antiproliferativen Effekte einer T3/TR-β-Aktivierung auf präneoplastische Knoten bei NASH von wesentlicher Bedeutung [5]. Auch hier wird die länger laufende Phase-III-Studie in F2-bis F3-Patienten (MAESTRO-NASH NCT03900429) Auskunft geben.…”