The role of TSH signaling in oncogenesis

The review considers the current knowledge about the structure of the thyroid-stimulating hormone (TSH) receptor, itsfunctions in various organs and tissues, the mechanisms of stimulating action of TSH on the synthesis of thyroid hormones,and the influence of TSH signaling on cell proliferation and differentiation in the context of evolutionary genetics and thehierarchical target organ regulation of pituitary hormones. Thyroid-stimulating hormone and its associated receptor (TSHR)are crucial for proliferation of thyrocytes and realization of their functional activity. In addition, according to modern ideas,the TSH/TSHR complex is considered an important modulator of oncogenesis and tumor progression. The interaction ofthe G-protein-coupled receptor (GPCR) and the ligand initiates a number of signaling cascades directly involved in cellproliferation and survival not only in normal tissues, but also in pathologically altered extra-thyroid organs and the thyroidgland. The relationship of hypo- and hyperthyroid states with the risk of promotion of tumors of various localization, thetypes of thyroid hormone influence on cellular metabolism are also considered. In addition to the most studied role –regulation of basal metabolism, the most important function of T3 and T4 is to control cell migration and differentiation viaboth genomic and non-genomic effects, which plays a key role in the process of ontogenesis and should be investigatedas a tumor growth mechanism. Most studies, both in vivo and in humans, observe the association of hypothyroidism withdecreased cancer incidence and tumor growth rate. Some publications demonstrate a smaller proportion of lymph nodeinvolvement, a higher rate of localized forms, lower mortality in cancer patients with hypothyroidism, while other studiesshow a correlation between hyperthyroidism and increased cancer risk, larger primary tumors, regional metastasis,and decreased survival of cancer patients. However, the study design features, lack of data on the age, gender, tumormolecular subtype, ethnicity, region of residence, iodine availability, grade of thyroid function suppression after theanticancer treatment are extremely important for each clinical case due to the ambiguity of the thyroid hormone effect ontumor progression in various cancers. It is important to note that although direct monitoring of thyroid function, includingfree T4 and TTH, is necessary, it is not sufficient to assess the thyroid status of a patient. The profile of plasma bindingproteins, tissue metabolism, receptor profile, the direct effect of thyrotropin releasing factor and TSH on tissues, thepresence, concentration, and type of the thyroid stimulating hormone receptor autoantibodies are important, and furtherscientific research is required in this direction. In this review, 106 publications from the Scopus, PubMed, Web of Sciencebiomedical literature databases were analyzed, and 72 publications were included.
Keywords: TSH, TSH receptor, oncogenesis, carcinogenesis, hyperthyroidism, hypothyroidism, TSH-signaling,CREB, thyroid dysfunction, thyroid cancer
Conflicts of interest. The authors have no conflicts of interest to declare.
Funding. There was no funding for this study