Activation of the mechanistic target of rapamycin complex 1 (mTORC1) in thyrocytes induces follicular hyperplasia and impairs thyroid hormone synthesis
The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine-threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathways overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well. To elucidate mTORC1s role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting Tuberous Sclerosis Complex 2 (TSC2), an intracellular inhibitor of mTORC1. The resulting TPO-TSC2KO mice exhibited a significant reduction in TSC2 levels, leading to a six-fold increase in mTORC1 activity. Thyroid glands of both male and female TPO-TSC2KO mice displayed rapid enlargement and continued growth throughout life, accompanied by heterogeneity among thyroid follicles, larger follicles, increased colloid and epithelium. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated Cyclin D3 expression in the TPO-TSC2KO mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone (TH) biosynthesis, including thyroglobulin, thyroid peroxidase, and sodium-iodide symporter (NIS), while TTF1, PAX8, and MCT8 mRNA levels remained unaffected. NIS protein expression was also diminished in TPO-TSC2KO mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in TPO-TSC2KO mice. Although T4, T3 and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in TPO-TSC2KO compared to littermate control mice. TPO-TSC2KO mice aged to 12 months or older developed aberrant thyroid conditions, including follicular hyperplasia, inflammation, and thyroid tumors. In conclusion, our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits TH biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation. Chronic mTORC1 activation leads to thyroid tumor formation, highlighting the role of mTORC1 in thyroid dysfunction and tumorigenesis.