Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.
Sangmi OckJihyun AhnSeok Hong LeeHyun Min KimHyun KangYoung-Kook KimHyun KookWoo Jin ParkShin KimShioko KimuraChan Kwon JungMinho ShongMartin HolzenbergerE Dale AbelTae Jin LeeBo Youn ChoHo-Shik KimJaetaek KimPublished in: International journal of cancer (2018)
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.
Keyphrases
- pi k akt
- binding protein
- growth hormone
- signaling pathway
- type diabetes
- transcription factor
- small cell lung cancer
- lymph node metastasis
- dna methylation
- squamous cell carcinoma
- preterm infants
- machine learning
- adipose tissue
- gene expression
- genome wide
- computed tomography
- oxidative stress
- weight loss
- low birth weight
- induced apoptosis
- gestational age
- endoplasmic reticulum stress