title: Targeted Foxe1 Overexpression in Mouse Thyroid Causes the Development of Multinodular Goiter But Does Not Promote Carcinogenesis.
abstract: Recent genome-wide association studies have identified several single nucleotide polymorphisms in the forkhead box E1 gene (FOXE1) locus, which are strongly associated with the risk for thyroid cancer. In addition, our recent work has demonstrated FOXE1 overexpression in papillary thyroid carcinomas. To assess possible contribution of Foxe1 to thyroid carcinogenesis, transgenic mice overexpressing Foxe1 in their thyroids under thyroglobulin promoter (Tg-Foxe1) were generated. Additionally, Tg-Foxe1 mice were exposed to x-rays at the age of 5 weeks or crossed with Pten(+/-) mice to examine the combined effect of Foxe1 overexpression with radiation or activated phosphatidylinositol-3-kinase/Akt pathway, respectively. In 5- to 8-week-old Tg-Foxe1 mice, severe hypothyroidism was observed, and mouse thyroids exhibited hypoplasia of the parenchyma. Adult 48-week-old mice were almost recovered from hypothyroidism, their thyroids were enlarged, and featured colloid microcysts and multiple benign nodules of macrofollicular-papilloid growth pattern, but no malignancy was found. Exposure of transgenic mice to 1 or 8 Gy of x-rays and Pten haploinsufficiency promoted hyperplastic nodule formation also without carcinogenic effect. These results indicate that Foxe1 overexpression is not directly involved in the development of thyroid cancer and that proper Foxe1 dosage is essential for achieving normal structure and function of the thyroid.
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Alyaksandr
authors.initials: A
authors.lastname: Nikitski
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saenko
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Shimamura
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsuse
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Rogounovitch
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Tetiana
authors.initials: T
authors.lastname: Bogdanova
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shibusawa
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Departments of Radiation Medical Sciences (A.N., M.M., K.S., S.Y., N.M.), Radiation Molecular Epidemiology (V.S., S.Y.), Molecular Medicine (M.S., Y.N.), Global Health, Medicine and Welfare (T.R.), and Department of Tumor and Diagnostic Pathology (M.N.), Atomic Bomb Disease Institute, Nagasaki University; Nagasaki University Graduate School of Biomedical Sciences (A.N.); and Nagasaki University Research Centre for Genomic Instability and Carcinogenesis (N.M.), Nagasaki 852-8523, Japan; Laboratory of Morphology of Endocrine System (T.B.), State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of Academy of Medical Sciences of Ukraine, Kyiv 254114, Ukraine; and Department of Medicine and Molecular Science (N.S., M.Y.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
authors.forename: Norisato
authors.initials: N
authors.lastname: Mitsutake
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D006042:Goiter / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D051858:Forkhead Transcription Factors; C472789:Foxe1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt