TSH signalling and cancer.
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 networks 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.
García-Jiménez
Custodia
C
Departamento de Ciencias de la Salud III, Universidad Rey Juan Carlos, Madrid, Spain.
Santisteban
Pilar
P
D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D011989:Receptors, Thyrotropin; D051153:Wnt Proteins; D013972:Thyrotropin; D000242:Cyclic AMP; D019204:GTP-Binding Proteins