TSH signalling and cancer

Abstract

Thyroid cancers are the most frequent endocrine neoplasms and mutations in the thyrotropin receptor (TSHR) are unusually frequent. Here we present the state-of-the-art concerning the role of TSHR in thyroid cancer and discuss it in light of the cancer stem cell theory or the classical view. We briefly review the gene and protein structure updating the cancer related TSHR mutations database. Intriguingly, hyperfunctioning TSHR mutants characterise differentiated cancers in contrast to undifferentiated thyroid cancers which very often bear silenced TSHR. It remains unclear whether TSHR alterations in thyroid cancers play a role in the onset or they appear as a consequence of genetic instability during evolution, but the presence of functional TSHR is exploited in therapy. We outline the signalling network build up in the thyrocyte between TSHR/PKA and other proliferative pathways such as Wnt, PI3K and MAPK. This network's integrity surely plays a role in the onset/evolution of thyroid cancer and needs further research. Lastly, future investigation of epigenetic events occurring at the TSHR and other loci may give better clues for molecular based therapy of undifferentiated thyroid carcinomas. Targeted demethylating agents, histone deacetylase inhibitors combined with retinoids and specific RNAis may help treatment in the future. RESUMOSinalização de TSH e Câncer. Os cânceres de tiróide são as neoplasias endócrinas mais frequentes e as mutações no receptor de tirotrofina (TSHR) são incomumente frequentes. Nesta revisão nós apresentamos o "estado da arte" com relação ao papel do TSHR no câncer de tiróide e o discutimos à luz da teoria da célula matriz do câncer ou a visão clássica. Revisamos brevemente a estrutura do gene e da proteína, atualizando a base de dados das mutações do TSHR relacionadas ao câncer. Curiosamente, mutações do TSHR com hiperfunção caracterizam cânceres diferenciados, em contraste com os cânceres de tiróide indiferenciados, os quais muito comumente mostram TSHR silenciados. Permanece obscuro se as alterações do TSHR em cânceres de tiróide têm algum papel no surgimento ou se elas aparecem como conseqüência da instabilidade genética durante seu desenvolvimento, mas a presença de TSHR funcional é explorada na terapia. Nós delineamos a rede de sinalizacão desenvolvida no tirócito entre TSHR/PKA e outras vias proliferativas como a Wnt, PI3k e MAPK. A integridade desta rede certamente tem um papel no surgimento/evolução do câncer de tiróide e necessita de novas pesquisas. Finalmente, novas investigacões sobre os eventos epigenéticos que ocorrem no TSHR e outros locais poderão trazer novas informações para uma terapia de base molecular nos carcinomas indiferenciados de tiróide. Agentes demetilantes direcionados, inibidores da histona-deacetilase, combinados com retinóides e RNAs específicos poderão auxiliar no tratamento futuro.

Hyperthyroidism Due to Papillary Thyroid Carcinoma Associated with Ductal Breast Carcinoma

“…These mutations lead to the constitutive activation of the intracellular cAMP cascade, inducing hormonogenesis in tumor cells [13] and thus explaining hyperthyroidism. Controversies exist whether TSH-R mutations themselves induce cell proliferation or whether they are followed by other mutations in important oncogenes of intracellular signaling pathways such as MAPK, PI3K and Wnt [16] resulting in abnormal proliferation and tumorigenesis. These pathways are integrated into the cAMP-PKA pathway and alterations in their cross-talk may result in cell proliferation and carcinogenesis.…”

Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

“…PKA transports into the nucleus, where it phosphorylates cAMP response element-binding (CREB). CREB binds to the promoter site of the thyroglobulin (TG) gene and regulates thyroglobulin gene expression (García-Jimenez and Santisteban 2007). TG is stored into the lumen of thyroid follicular cells.…”

Differentiation Therapy in Thyroid Carcinoma

“…TSH and TSH-R are required for proliferation of thyrocytes and expression of differentiation markers like NIS (Garcia-Jimenez & Santisteban, 2007). The TSH-R is a 7-transmembrane spanning glycoprotein, also expressed in bone, brain, kidney, testes and cells of the immune system.…”