Journal article
Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation
International journal of cancer, Vol.143(10), pp.2458-2469
11/15/2018
DOI: 10.1002/ijc.31779
PMCID: PMC6698377
PMID: 30070361
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.
Details
- Title: Subtitle
- Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation
- Creators
- Sangmi Ock - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, KoreaJihyun Ahn - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, KoreaSeok Hong Lee - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, KoreaHyun Min Kim - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, KoreaHyun Kang - Department of Anesthesiology, College of Medicine, Chung-Ang University, Seoul, KoreaYoung-Kook Kim - Department of Biochemistry, Chonnam National University Medical School, Gwangju, KoreaHyun Kook - Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, KoreaWoo Jin Park - Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, KoreaShin Kim - Department of Immunology, Keimyung University School of Medicine, Daegu, KoreaShioko Kimura - Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USAChan Kwon Jung - Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, KoreaMinho Shong - Research Center for Endocrine and Metabolic Diseases, Department of Internal Medicine, Chungnam National University, Daejeon, KoreaMartin Holzenberger - INSERM and Sorbonne University, Saint-Antoine Research Center, Paris, FranceE. Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA, USATae Jin Lee - Department of Pathology, College of Medicine, Chung-Ang University, Seoul, KoreaBo Youn Cho - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, KoreaHo-Shik Kim - Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, KoreaJaetaek Kim - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
- Resource Type
- Journal article
- Publication Details
- International journal of cancer, Vol.143(10), pp.2458-2469
- DOI
- 10.1002/ijc.31779
- PMID
- 30070361
- PMCID
- PMC6698377
- ISSN
- 0020-7136
- eISSN
- 1097-0215
- Grant note
- DOI: 10.13039/501100003725, name: National Research Foundation of Korea, award: 2012R1A5A2047939, NRF‐2012R1A1A2043642, 2016R1A4A1009895
- Language
- English
- Date published
- 11/15/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024535002771
Metrics
9 Record Views