Abstract
Several physiological processes, including cellular growth, embryonic development, differentiation, metabolism and proliferation, are modulated by genomic and nongenomic actions of thyroid hormones (TH). Several intracellular and extracellular candidate proteins are regulated by THs. 3,3,5-Triiodo-L-thyronine (T3) can interact with nuclear thyroid hormone receptors (TR) to modulate transcriptional activities via thyroid hormone response elements (TRE) in the regulatory regions of target genes or bind receptor molecules showing no structural homology to TRs, such as the cell surface receptor site on integrin αvβ3. Additionally, L-thyroxine (T4) binding to integrin αvβ3 is reported to induce gene expression through initiating non-genomic actions, further influencing angiogenesis and cell proliferation. Notably, thyroid hormones not only regulate the physiological processes of normal cells but also stimulate cancer cell proliferation via dysregulation of molecular and signaling pathways. Clinical hypothyroidism is associated with delayed cancer growth. Conversely, hyperthyroidism is correlated with cancer prevalence in various tumor types, including breast, thyroid, lung, brain, liver and colorectal cancer. In specific types of cancer, both nuclear thyroid hormone receptor isoforms and those on the extracellular domain of integrin αvβ3 are high risk factors and considered potential therapeutic targets. In addition, thyroid hormone analogs showing substantial thyromimetic activity, including triiodothyroacetic acid (Triac), an acetic acid metabolite of T3, and tetraiodothyroacetic acid (Tetrac), a derivative of T4, have been shown to reduce risk of cancer progression, enhance therapeutic effects and suppress cancer recurrence. Here, we have reviewed recent studies focusing on the roles of THs and TRs in five cancer types and further discussed the potential therapeutic applications and underlying molecular mechanisms of THs.
Highlights
Thyroid hormone (TH) in adults is necessary for the regulation of multiple physiological effects, such as cell growth, structure, and metabolism [1]
The actions of thyroid hormone are classified into two main mechanisms: (1) A non-genomic effect initiated at the plasma membrane that regulates downstream gene expression via integrin αvβ3; and (2) transcriptional activity induced by interactions with nuclear thyroid hormone receptor proteins and further binding to thyroid hormone response elements of specific downstream genes
This review provides an overview on the individual mechanisms underlying physiological TH/thyroid hormone receptors (TR)-mediated regulation of different cancer types
Summary
Thyroid hormone (TH) in adults is necessary for the regulation of multiple physiological effects, such as cell growth, structure, and metabolism [1]. The main thyroid hormones produced by the thyroid gland are thyroxine (T4), 3,5,3 -triiodothyronine (T3), and reverse 3,5,3 -triiodothyronine (rT3), which are controlled by thyroid-stimulating hormone (TSH). The actions of thyroid hormone are classified into two main mechanisms: (1) A non-genomic effect initiated at the plasma membrane that regulates downstream gene expression via integrin αvβ; and (2) transcriptional activity induced by interactions with nuclear thyroid hormone receptor proteins and further binding to thyroid hormone response elements of specific downstream genes. Thyroid hormone activity is beneficial for normal cell development When both the levels of THs and thyroid hormone receptors in the body are out of control, it causes multiple diseases, including cardiovascular disease, diabetes mellitus and chronic liver disease [5]. The current review focuses on the potential association between thyroid hormones and progression of different cancer types
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