Actions of L-thyroxine (T4) and Tetraiodothyroacetic Acid (Tetrac) on Gene Expression in Thyroid Cancer Cells.

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

doi:10.3390/genes11070755

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 T4′s 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.

Highlights

The clinical behavior of thyroid gland cancers is seen to reflect gene mutation and/or epigenetic changes [1,2], and effects of circulating or local trophic factors [3,4]
Because tetrac is a specific inhibitor of the actions of T4 at integrin αvβ3, we propose that T4 has actions in MCT cells that are anti-apoptotic, as has been shown to be the case in papillary and follicular thyroid cancer cells
When differentiated thyroid carcinomas recur in the context of T4-conditioned suppression of TSH, we have suggested that the tumors are no longer TSH-dependent and, may be T4-dependent [3]

Summary

Introduction

The clinical behavior of thyroid gland cancers is seen to reflect gene mutation and/or epigenetic changes [1,2], and effects of circulating or local trophic factors [3,4]. The cell surface integrin, tetrac was seen to have low-grade T3-like activity at the nuclear receptors [6]. Plasma membrane integrin αvβ contains a cell surface receptor for thyroid hormones carcinoma cells. Plasma membrane integrin αvβ contains a cell surface receptor for thyroid and is overexpressed by cancer cells. T3 is the principal ligand of nuclear thyroid hormone receptors cells; TRs are not shown in the figure. TRs and the TSH receptor are not structurally related to generating receptor on the plasma membrane of thyroid cancer cells. 2. T4 Actions at the Integrin αvβ in Papillary and Follicular Thyroid Carcinoma Cells. The hormone receptors involved are exclusively nuclear TRs. Lin et al [16] showed in 2007 that differentiated papillary and follicular human thyroid carcinoma al.

Proliferative activity of in

Discussion