Thyroid Hormone Deiodinases and Cancer

Abstract

Deiodinases constitute a group of thioredoxin fold-containing selenoenzymes that play an important function in thyroid hormone homeostasis and control of thyroid hormone action. There are three known deiodinases: D1 and D2 activate the pro-hormone thyroxine (T4) to T3, the most active form of thyroid hormone, while D3 inactivates thyroid hormone and terminates T3 action. A number of studies indicate that deiodinase expression is altered in several types of cancers, suggesting that (i) they may represent a useful cancer marker and/or (ii) could play a role in modulating cell proliferation – in different settings thyroid hormone modulates cell proliferation. For example, although D2 is minimally expressed in human and rodent skeletal muscle, its expression level in rhabdomyosarcoma (RMS)-13 cells is threefold to fourfold higher. In basal cell carcinoma (BCC) cells, sonic hedgehog (Shh)-induced cell proliferation is accompanied by induction of D3 and inactivation of D2. Interestingly a fivefold reduction in the growth of BCC in nude mice was observed if D3 expression was knocked down. A decrease in D1 activity has been described in renal clear cell carcinoma, primary liver cancer, lung cancer, and some pituitary tumors, while in breast cancer cells and tissue there is an increase in D1 activity. Furthermore D1 mRNA and activity were found to be decreased in papillary thyroid cancer while D1 and D2 activities were significantly higher in follicular thyroid cancer tissue, in follicular adenoma, and in anaplastic thyroid cancer. It is conceivable that understanding how deiodinase dysregulation in tumor cells affect thyroid hormone signaling and possibly interfere with tumor progression could lead to new antineoplastic approaches.

Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling

“…Below we focus on the role played by D2 in the T4-mediated TRH–TSH feedback mechanism, adaptive thermogenesis and myogenesis and muscle regeneration. The reader is referred to other publications for a more comprehensive analysis of the role played by D2 in different biological systems [10,45,65–71]. …”

Stromal iodothyronine deiodinase 2 (DIO2) promotes the growth of intestinal tumors in ApcΔ716 mutant mice

“…Iodothyronine deiodinase 3 inactivates T3 and terminates its effects. Iodothyronine deiodinase 2 is expressed in multiple tissues, whereas DIO1 expression is virtually restricted to the liver and kidney . Iodothyronine deiodinase 2 has a ~500‐fold higher affinity for T4 than DIO1 .…”

“…A growing body of evidence indicates altered expression of DIOs in several types of cancers and many cancer cell lines, including those from CRC highly express DIO3 . An in vitro study showed that inhibition of Wnt signaling, the key initial step for CRC development, reduced DIO3 levels and induced DIO2 levels in Caco‐2 cells .…”

Genetics of Thyroid Disorders

“…On the other hand, D2 is increased in FTC, in anaplastic thyroid cancer (ATC), and in medullary thyroid cancer (MTC), whereas in PTC, glioblastomas and astrocytomas is diminished. 21 Meanwhile, in ATC, which is quite aggressive, alterations have been identified in FOXM1, which codes for the protein Forkhead Box M1, that be-longs to a family of transcription factors involved in the control of cell proliferation, chromosomal stability, and angiogenesis and is highly increased in non-differentiated thyroid cancer. Moreover, high levels of FOXM1 have been linked to a loss of p53 function and uncontrolled activation of the phosphatidylinositol-3 kinase/AKT/FOXO3a pathway.…”