Carcinogenesis Advance Access originally published online on July 6, 2009
Carcinogenesis 2009 30(9):1614-1619; doi:10.1093/carcin/bgp167
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Published by Oxford University Press 2009.
Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice
1 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 Global VetPathology, Montgomery Village, MD 20886, USA
3 Present address: Clinical Laboratory of Pathology, Tochigi Cancer Center, 4-9-13 Yonan, Utsunomiya 320-0834, Japan
4 Present address: Department of Pathology, Southern TOHOKU Research Institute for Neuroscience, Southern TOHOKU General Hospital, 7-115 Yatsuyamada, Koriyama 963-8563, Japan
* To whom correspondence should be addressed. Building 37, Room 3118 National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. Tel: +1 301 496 0958; Fax: +1 301 496 8419; Email: kimuras{at}mail.nih.gov
NKX2-1 is a homeodomain transcription factor that is critical for genesis of the thyroid and transcription of the thyroid-specific genes. Nkx2-1-thyroid-conditional hypomorphic mice were previously developed in which Nkx2-1 gene expression is lost in 50% of the thyroid cells. Using this mouse line as compared with wild-type and Nkx2-1 heterozygous mice, a thyroid carcinogenesis study was carried out using the genotoxic carcinogen N-bis(2-hydroxypropyl)-nitrosamine (DHPN), followed by sulfadimethoxine (SDM) or the non-genotoxic carcinogen amitrole (3-amino-1,2,4-triazole). A significantly higher incidence of adenomas was obtained in Nkx2-1-thyroid-conditional hypomorphic mice as compared with the other two groups of mice only when they were treated with DHPN + SDM, but not amitrole. A bromodeoxyuridine incorporation study revealed that thyroids of the Nkx2-1-thyroid-conditional hypomorphic mice had >2-fold higher constitutive cell proliferation rate than the other two groups of mice, suggesting that this may be at least partially responsible for the increased incidence of adenoma in this mouse line after genotoxic carcinogen exposure. Thus, NKX2-1 may function to control the proliferation of thyroid follicular cells following damage by a genotoxic carcinogen.
Abbreviations: amitrole, 3-amino-1,2,4-triazole; BrdU, bromodeoxyuridine; DHPN, N-bis(2-hydroxypropyl)-nitrosamine; PCR, polymerase chain reaction; SDM, sulfadimethoxine; TPO, thyroid peroxidase; TSH, thyrotropin or thyroid-stimulating hormone
Received April 10, 2009; revised May 31, 2009; accepted June 25, 2009.