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

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          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.

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          Author and article information

          Journal
          0042124
          4284
          Int J Cancer
          Int. J. Cancer
          International journal of cancer
          0020-7136
          1097-0215
          13 August 2019
          22 September 2018
          15 November 2018
          15 November 2019
          : 143
          : 10
          : 2458-2469
          Affiliations
          [1 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
          [2 ]Department of Anesthesiology, College of Medicine, Chung-Ang University, Seoul, Korea
          [3 ]Department of Biochemistry, Chonnam National University Medical School, Gwangju, Korea
          [4 ]Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Korea
          [5 ]Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea
          [6 ]Department of Immunology, Keimyung University School of Medicine, Daegu, Korea
          [7 ]Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
          [8 ]Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
          [9 ]Research Center for Endocrine and Metabolic Diseases, Department of Internal Medicine, Chungnam National University, Daejeon, Korea
          [10 ]INSERM and Sorbonne University, Saint-Antoine Research Center, Paris, France
          [11 ]Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, University of Iowa Carver College of Medicine, Iowa City, IA, USA
          [12 ]Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Korea
          [13 ]Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea
          Author notes

          Jihyun Ahn’s current address is: Korea Medical Institute, 142-35 Samsung dong, Gangnamgu, Seoul, Korea

          Seok Hong Lee’s current address is: Dream Hospital, 153 Daemyung ro, Nam gu, Daegu, Korea

          Correspondence to: Ho-Shik Kim, Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea, Tel.: 82-2-2258-7294; hoshik@ 123456catholic.ac.kr or Jaetaek Kim, Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, 156-755, Korea, Tel.: 82-2-6299-1397, Fax: 82-2-6299-1390, jtkim@ 123456cau.ac.kr
          Author information
          http://orcid.org/0000-0001-5247-0408
          Article
          PMC6698377 PMC6698377 6698377 nihpa1036980
          10.1002/ijc.31779
          6698377
          30070361
          b1541f0b-2911-4395-bffd-b7a044ed9cec
          History
          Categories
          Article

          hyperplasia,folliculogenesis,thyroid,IGF-1 receptor,insulin receptor

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