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

• Published in: International journal of cancer 2018-11, Vol.143 (10), p.2458-2469
• Main Authors: Ock, Sangmi, Ahn, Jihyun, Lee, Seok Hong, Kim, Hyun Min, Kang, Hyun, Kim, Young‐Kook, Kook, Hyun, Park, Woo Jin, Kim, Shin, Kimura, Shioko, Jung, Chan Kwon, Shong, Minho, Holzenberger, Martin, Abel, E. Dale, Lee, Tae Jin, Cho, Bo Youn, Kim, Ho‐Shik, Kim, Jaetaek
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Epidermal growth factor receptors; ErbB protein; ErbB Receptors - metabolism; Folliculogenesis; Humans; Hyperplasia; IGF‐1 receptor; Insulin; insulin receptor; Insulin-like growth factors; Lesions; Male; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Neonates; Papillary thyroid carcinoma; Receptor, IGF Type 1 - deficiency; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - deficiency; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Rodents; Signal Transduction; Thyroid; Thyroid cancer; Thyroid Cancer, Papillary - metabolism; Thyroid Cancer, Papillary - pathology; Thyroid Epithelial Cells - metabolism; Thyroid Epithelial Cells - pathology; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Thyroid-stimulating hormone; Thyrotropin - biosynthesis; Thyrotropin - metabolism; TOR protein
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31779

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. What's new? Loss of insulin‐like growth factor‐1 receptor (IGF‐1R) in the thyroid results in chronic signaling by thyroid stimulating hormone. Little is known, however, about the consequences of IGF‐1R deletion or the loss insulin receptor (IR). Here, using a thyrocyte‐specific IR and IGF‐1R double knockout mouse model, the authors show that IR/IGF‐1R signaling in the thyroid is necessary for normal folliculogenesis. While thyroid size was smaller in neonatal knockout animals, IR/IGF‐1R loss paradoxically induced thyrocyte proliferation at postnatal day 14, a process mediated by mTOR‐dependent signaling. Papillary thyroid carcinoma‐like lesions were later detected in aged double knockout mice.