Thyrocyte‐specific deletion of insulin and IGF‐1 receptors induces papillary thyroid carcinoma‐like lesions through EGFR pathway activation

Abstract

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

Insulin-Like Growth Factor Pathway and the Thyroid

“…These processes in turn are mediated through the activities of the sodium iodide symporter and thyroperoxidase, respectively. In a study of mice with conditional double-thyroid knockout of IGF-IR and IR, neonatal thyroid glands were smaller, exhibited repressed FOXE1 expression, and manifested defective folliculogenesis (38). At postnatal day 14, mTORdependent epithelial cell proliferation and serum TSH were detectable.…”

Transcription factor GLIS3: Critical roles in thyroid hormone biosynthesis, hypothyroidism, pancreatic beta cells and diabetes

“…Since NDH patients acquire a wide range of pathologies, including hyperglycemia and hypoinsulinemia, these phenotypes may also affect the development and function of the thyroid gland. This hypothesis is supported by studies showing that the insulin and insulin-like growth factor-1 receptors (INNSR and IGF1R) play a critical role in thyroid folliculogenesis (Ock, et al, 2018) and a GWAS showing the importance of the insulin receptor (INSR) locus in the regulation of thyroid function (Porcu, et al, 2013). The latter study also identified an association between the GLIS3 variant, rs1571583, and the regulation of thyroid dysfunction (Porcu, et al, 2013).…”

Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism

“…Similarly, signaling through IGF-1R is essential for normal thyroid formation and function, particularly by supporting thyroid cell survival through TSHR signaling 42,70 . IGF-1R and insulin receptor (IR) double-thyroid knockout mice showed hypoplastic thyroid glands at birth, folliculogenesis defects and specifically repressed Foxe1 expression 71 . Besides, in vitro studies suggest that IGF-1 is required for the differentiation of mouse embryonic stem cells into thyroid epithelial cells, supporting the role of this signal in thyroid development 16,17 .…”