Actions of l-thyroxine (T4) and tetraiodothyroacetic acid (tetrac) on gene expression in thyroid cancer cells

Paul J. Davis, Hung Yun Lin, Aleck Hercbergs, Shaker A. Mousa

Research output: Contribution to journalReview articlepeer-review

Abstract

The clinical behavior of thyroid cancers is seen to reflect inherent transcriptional activities of mutated genes and trophic effects on tumors of circulating pituitary thyrotropin (TSH). The thyroid hormone, L-thyroxine (T4), has been shown to stimulate proliferation of a large number of different forms of cancer. This activity of T4 is mediated by a cell surface receptor on the extracellular domain of integrin αvβ3. In this brief review, we describe what is known about T4 as a circulating trophic factor for differentiated (papillary and follicular) thyroid cancers. Given T4s cancer-stimulating activity in differentiated thyroid cancers, it was not surprising to find that genomic actions of T4 were anti-apoptotic. Transduction of the T4-generated signal at the integrin primarily involved mitogen-activated protein kinase (MAPK). In thyroid C cell-origin medullary carcinoma of the thyroid (MTC), effects of thyroid hormone analogues, such as tetraiodothyroacetic acid (tetrac), include pro-angiogenic and apoptosis-linked genes. Tetrac is an inhibitor of the actions of T4 at αvβ3, and it is assumed, but not yet proved, that the anti-angiogenic and pro-apoptotic actions of tetrac in MTC cells are matched by T4 effects that are pro-angiogenic and anti-apoptotic. We also note that papillary thyroid carcinoma cells may express the leptin receptor, and circulating leptin from adipocytes may stimulate tumor cell proliferation. Transcription was stimulated by leptin in anaplastic, papillary, and follicular carcinomas of genes involved in invasion, such as matrix metalloproteinases (MMPs). In summary, thyroid hormone analogues may act at their receptor on integrin αvβ3 in a variety of types of thyroid cancer to modulate transcription of genes relevant to tumor invasiveness, apoptosis, and angiogenesis. These effects are independent of TSH.

Original languageEnglish
Article number755
Pages (from-to)1-9
Number of pages9
JournalGenes
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Angiogenesis
  • Apoptosis
  • Integrin αvβ3
  • L-thyroxine (T4)
  • Tetraiodothyroacetic acid (tetrac)
  • Thyroid cancer

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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