Endocrine Abstracts (2009) 20 S14.4

Type 3 deiodinase and cancer

Domenico Salvatore

University of Naples Federico II, Naples, Italy.

Thyroid hormones (TH) are endocrine molecules necessary for multiple biological processes that are crucial to tumor growth and differentiation. Several reports pointed out a pivotal role of thyroid status in the tumoral behavior.

TH action is regulated by the action of the deiodinases. Type 2 deiodinase (D2) activates thyroxine (T4) by converting it to T3, whereas D3, by inactivating T3, terminates thyroid hormone action.Thus, the deiodinase family of selenoprotein constitutes a potent mechanism to control thyroid hormone signaling, allowing cells to customize their own T3 intracellular concentration in a spatial- and temporal-dependent/specific fashion.

D3 is an oncofetal protein frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. D3 mRNA and/or activity has been reported in several tumoral cell lines (breast and colon carcinoma, hepatocarcinoma and neuroblastoma) and human tumors, including astrocytomas, gliomas, TSH-secreting pituitary tumors. High levels of D3 expression in vascular tumors, a condition that can cause consumptive hypothyroidism.

At the same time, tissues expressing D3 have lower T3 concentrations than what would be expected from plasma contribution; thus, D3- expressing tissues have a gene expression profile typical of hypothyroid cells (28, 175). This is explained by the inactivation of T3 and T4 that takes place at the plasma membrane level immediately after these hormones enter the cell.

We have recently demonstrated that the Shh pathway, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human basal cell carcinoma, the most frequent human cancer. We further demonstrate that Gli-induced D3 over-expression reduces intracellular active thyroid hormone (T3), thus resulting in increased cyclin D1 and keratinocyte proliferation.

Whether and how the control of local TH homeostasis contributes to the neoplastic growth will be discussed and is the object of active investigations.

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