Role of Transforming Growth Factor Beta in the Regulation of Thyroid Function and Growth

Abstract

Transforming growth factor beta (TGF-beta) exists in nature as three isoforms. They exert their effects by binding to a type II receptor located at the cell membrane. The TGF-beta-type II receptor complex then recruits type I receptor, and this new complex stimulates the phosphorylation of Smads 2 and 3, which are subsequently transferred to the nucleus, where they regulate gene transcription. The thyroid gland expresses the TGF-beta1 gene mRNA and synthesizes the protein, which under physiologic conditions regulates thyroid growth and function. Different studies have demonstrated that TGF-beta1 inhibits cell proliferation and a number of functional parameters. These include cyclic adenosine monophosphate (AMP) formation, iodine uptake and organification, hormone secretion, and the expression of thyroglobulin, thyroid peroxidase, and Na(+)/I(-) symporter. The expression of the TGF-beta1 gene and protein may be stimulated by iodine under normal conditions. Since TGF-beta1 mimics some of the inhibitory actions of iodine, its participation in thyroid autoregulation has been proposed; however, this concept is still debated. In thyroid tumors, the inhibitory action of TGF-beta1 on cell proliferation is progressively lost as the tumor becomes more undifferentiated. The alterations in the signaling pathway of TGF-beta1 are not the same in tumors from different species. Even within the same species, such as the pig thyroid, the results may be different depending on whether monolayers or follicular suspensions are employed. The data suggest that it is not entirely possible to apply the results obtained in animal studies to normal or pathological human thyroid tissue. More studies are required to provide the information needed to develop treatments, based on targeting the signaling pathway of TGF-beta1, for undifferentiated thyroid cancer and other thyroid diseases.

Expression of SMAD proteins, TGF-beta/activin signaling mediators, in human thyroid tissues

“…TGF-β and activin exert antiproliferative effects in epithelial cells, including follicular thyroid cells (24). However, TGF-β and activin are overexpressed in several carcinomas (17,19,25).…”

Demonstration of Innate Immune Responses in the Thyroid Gland: Potential to Sense Danger and a Possible Trigger for Autoimmune Reactions

“…Realtime PCR analyses revealed that iodide increased the mRNA levels of TGFB1 (Fig. 5B), which regulates immune responses and inhibits thyroid growth and function by downregulating thyroid-specific genes, such as SLC5A5, TG, and TPO (40)(41)(42)(43). Iodide also increased annexin-A1 (ANXA1), which is cleaved and released from apoptotic cells and inhibits the activation of monocytes and neutrophils (Fig.…”

Disruption of transforming growth factor-β signaling in thyroid follicular epithelial cells or intrathyroidal fibroblasts does not promote thyroid carcinogenesis

“…It has long been well known that TGF-β suppresses growth of normal thyroid follicular epithelial cells [11,12]. However, the effect of TGF-β on thyroid cancer cell behavior is controversial.…”

“…In the thyroids, as for other tissues, expression of TGF-β ligands and their receptors and their effects on growth of normal cells and established cancer cells have previously been studied [11,12], but yet the effect of TGF-β signaling on early thyroid carcinogenesis remained to be determined. In this current study, therefore, Tgfbr2 floxE2/floxE2 mice were crossed with FSP1-Cre or thyroid peroxidase (TPO)-Cre mice to study the significance of TGF-β signaling in thyroid follicular epithelial cells and surrounding fibroblasts for thyroid early carcinogenesis.…”