T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to further increase in the next years. Chronic inflammation, induced by multiple viruses or metabolic alterations, and epigenetic and genetic modifications, cooperate in cancer development via a combination of common and distinct aetiology-specific pathways. In spite of the advances of classical therapies, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. However, the benefits obtained from this treatment are still disappointing, as it extends the median life expectancy of patients by only few months. It is thus mandatory to find alternative effective treatments. Although the role played by thyroid hormones (THs) and their nuclear receptors (TRs) in human cancer is still unclear, mounting evidence indicates that they behave as oncosuppressors in HCC. However, the molecular mechanisms by which they exert this effect and the consequence of their activation following ligand binding on HCC progression remain elusive. In this review, we re-evaluate the existing evidence of the role of TH/TRs in HCC development; we will also discuss how TR alterations could affect fundamental biological processes, such as hepatocyte proliferation and differentiation, and consequently HCC progression. Finally, we will discuss if and how TRs can be foreseen as therapeutic targets in HCC and whether selective TR modulation by TH analogues may hold promise for HCC treatment.

TUG1 Is a Regulator of AFP and Serves as Prognostic Marker in Non-Hepatitis B Non-Hepatitis C Hepatocellular Carcinoma

“…Human TRs are encoded by TRα1 and TRβ1 genes located on chromosomes 17 and 3, respectively [3]. Aberrant expression and/or mutation of TRs has been documented in pituitary tumors [4], hepatocellular carcinoma (HCC) [5] and thyroid cancer [6]. Hypothyroidism is associated with a significantly elevated risk for HCC, especially in hepatitis virus-negative subjects, non-drinkers, non-diabetics and non-smokers [7], along with non-alcoholic steatohepatitis (NASH) [8].…”

The significance of TRIP11 and T3 signaling pathway in renal cancer progression and survival of patients.

“…Hypoxia and activation of HIFs are a hallmark of solid tumours, resulting in stimulation of multiple genes that promote cancer progression [9]. Likewise, T3 and its receptors also influence multiple genes involved in cancer development and progression [1,10,11]. Remarkably, both these pathways share common gene targets, such as VEGF (vascular endothelial growth factor) or GLUT1 (glucose transporter 1) [12][13][14][15].…”

Hypothyroidism is associated with worse outcomes of hepatocellular carcinoma patients after liver transplantation

“…The survival curve shown in Figure shows that the largest difference between the hypothyroid and non‐hypothyroid groups occurred in the early years after liver transplantation. Based on previous publications , we can speculate that hypothyroidism may be a factor that accelerates the malignant process of HCC. Even though its role in other cancers is controversial, the effects of hypothyroidism on the incidence and outcomes of HCC are consistent.…”