Thyroid hormones (TH) play a major role during normal development by regulating several cellular processes including cell proliferation, differentiation, apoptosis and metabolism [1]. On target cells, a number of molecular players take part in the regulation of TH action. Among these are the iodothyronine deiodinases D1, D2, and D3 responsible for the conversion of T4 to the biologically active T3, by removing an iodine at the outer ring (D1 or D2), or for the inactivation of both TH by removing iodine at the inner ring of the molecule (D1 or D3). Once formed, T3 interact with specific nuclear receptors (TRs) that act as ligand dependent transcription factors, affecting the transcription of target genes [2]. TH may also affect cellular functions by binding to plasma membrane integrin receptors regulating intracellular signaling pathways [2].
Clinical evidence showed an association between alterations in TH action and the pathogenesis of several cancer types [3-5]. Recently, the Von Hippel Lindau protein (pVHL), a subunit of the E3 ubiquitin ligase targeting proteins to be eliminated via proteasome degradation, has been shown to affect levels and activity deiodinases [6-8]. Consistent with the hypothesis that alterations of VHL may affect the TH activation, an abnormal TH metabolism has been documented in kidney cancer, where inactivating mutations of VHL are frequent [6].
Aims of the present research project are to evaluate: 1) the association between the expression levels of deiodinases and VHL in a case study of papillary thyroid cancer, compared with their normal matched tissues; 2) the consequences of VHL alterations on intracellular levels and activity of TH.
References
1. Endocr Rev 1987, 8:288-308.
2. Physiol Rev 2001, 81:1097-1142.
3. Front Endocrinol 2019, 10:59.
4. Compr Physiol 2016, 6:1221-1237.
5. Endocr Relat Cancer 2013, 20:R19-R29.
6. Onco Targets Ther 2020, 13:5669-5690.
7. PLoS One 2017, 12:e0190179.
8. PLoS One 2011, 6:e24541.
Deiodinases play a crucial role in regulating intracellular TH action, and alterations in TH action has been observed in a variety of human cancers, including thyroid cancers. As above mentioned, some experimental evidence indicates that mutations or altered expression of VHL proteins may affect deiodinases protein levels thus affecting TH action. In a recent study, we showed that alterations of the expression of the different VHL isoforms take place during thyroid cancer progression (Mol Cell Endocrinol 2017, 443:121-127). Thus is likely that the observed alteration in VHL expression can contribute to regulate TH action in thyroid cancer cells. For these reasons, the aims of the present research proposal are those to ascertain the presence of any correlation among the expression level of VHL and that of deiodinases, as well as to shed light on the possible molecular mechanisms underlying VHL/deiodinases interactions and their cellular functional consequences. This could be of some clinical importance as it could pave the way for new prognostic and therapeutic approaches which are urgently needed for the more aggressive and poorly differentiated thyroid cancers.