Skip to main content

Advertisement

SpringerLink
Log in

Iodothyronine deiodinases and cancer

  • Review Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Thyroid hormones (TH) regulate key cellular processes, including proliferation, differentiation, and apoptosis in virtually all human cells. Disturbances in TH pathway and the resulting deregulation of these processes have been linked with neoplasia. The concentrations of TH in peripheral tissues are regulated via the activity of iodothyronine deiodinases. There are 3 types of these enzymes: type 1 and type 2 deiodinases are involved in TH activation while type 3 deiodinase inactivates TH. Expression and activity of iodothyronine deiodinases are disturbed in different types of neoplasia. According to the limited number of studies in cancer cell lines and mouse models changes in intratumoral and extratumoral T3 concentrations may influence proliferation rate and metastatic progression. Recent findings showing that increased expression of type 3 deiodinases may lead to enhanced tumoral proliferation support the idea that deiodinating enzymes have the potential to influence cancer progression. This review summarizes the observations of impaired expression and activity in different cancer types, published to date, and the mechanisms behind these alterations, including impaired regulation via TH receptors, transforming growth factor-β, and Sonic-hedgehog pathway. Possible roles of deiodinases as cancer markers and potential modulators of tumor progression are also discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010, 31: 139–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Marsili A, Zavacki AM, Harney JW, Larsen PR. Physiological role and regulation of iodothyronine deiodinases: a 2011 update. J Endocrin Invest 2011, 34: 395–407.

    CAS  Google Scholar 

  3. Gereben B, Zavacki AM, Ribich S, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008, 29: 898–938.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 2005, 115: 2524–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Laurberg P, Vestergaard H, Nielsen S, et al. Sources of circulating 3,5,3′-triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. J Clin Endocrinol Metab 2007, 92: 2149–56.

    CAS  PubMed  Google Scholar 

  6. St Germain DL, Galton VA, Hernandez A. Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology 2009, 150: 1097–107.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Williams GR. Actions of thyroid hormones in bone. Endokrynol Pol 2009, 60: 380–8.

    CAS  PubMed  Google Scholar 

  8. Bassett JH, Boyde A, Howell PG, et al. Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts. Proc Natl Acad Sci U S A 2010, 107: 7604–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Horn S, Heuer H. Thyroid hormone action during brain development: more questions than answers. Mol Cell Endocrinol 2010, 315: 19–26.

    CAS  PubMed  Google Scholar 

  10. Puzianowska-Kuznicka M, Pietrzak M, Turowska O, Nauman A. Thyroid hormones and their receptors in the regulation of cell proliferation. Acta Biochim Pol 2006, 53: 641–50.

    CAS  PubMed  Google Scholar 

  11. Dentice M, Ambrosio R, Salvatore D. Role of type 3 deiodinase in cancer. Expert Opin Ther Targets 2009, 13: 1363–73.

    CAS  PubMed  Google Scholar 

  12. Ohba K, Yoshioka T, Muraki T. Identification of two novel splicing variants of human type II iodothyronine deiodinase mRNA. Mol Cell Endocrinol 2001, 172: 169–75.

    CAS  PubMed  Google Scholar 

  13. Gereben B, Kollár A, Harney JW, Larsen PR. The mRNA structure has potent regulatory effects on type 2 iodothyronine deiodinase expression. Mol Endocrinol 2002, 16: 1667–79.

    CAS  PubMed  Google Scholar 

  14. Piekielko-Witkowska A, Master A, Wojcicka A, et al. Disturbed expression of type 1 iodothyronine deiodinase splice variants in human renal cancer. Thyroid 2009, 19: 1105–13.

    CAS  PubMed  Google Scholar 

  15. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 2002, 23: 38–89.

    CAS  PubMed  Google Scholar 

  16. Zhuo P, Diamond AM. Molecular mechanisms by which selenoproteins affect cancer risk and progression. Biochim Biophys Acta 2009, 1790: 1546–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Moustafa ME, Carlson BA, El-Saadani MA, et al. Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA. Mol Cell Biol 2001, 21: 3840–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Amaral AF, Cantor KP, Silverman DT, Malats N. Selenium and bladder cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010, 19: 2407–15.

    CAS  PubMed  Google Scholar 

  19. Steevens J, van den Brandt PA, Goldbohm RA, Schouten LJ. Selenium status and the risk of esophageal and gastric cancer subtypes: the Netherlands cohort study. Gastroenterology 2010, 138: 1704–13.

    CAS  PubMed  Google Scholar 

  20. Steinbrecher A, Méplan C, Hesketh J, et al. Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev 2010, 19: 2958–68.

    CAS  PubMed  Google Scholar 

  21. García-Solís P, Alfaro Y, Anguiano B, et al. Inhibition of N-methyl-N-nitrosourea-induced mammary carcinogenesis by molecular iodine (I2) but not by iodide (I-) treatment Evidence that I2 prevents cancer promotion. Mol Cell Endocrinol 2005, 236: 49–57.

    PubMed  Google Scholar 

  22. Shrivastava A, Tiwari M, Sinha RA, et al. Molecular iodine induces caspase-independent apoptosis in human breast carcinoma cells involving the mitochondria-mediated pathway. J Biol Chem 2006, 281: 19762–71.

    CAS  PubMed  Google Scholar 

  23. Galton VA, Schneider MJ, Clark AS, St Germain DL. Life without thyroxine to 3,5,3′-triiodothyronine conversion: studies in mice devoid of the 5′-deiodinases. Endocrinology 2009, 150: 2957–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Hercbergs AH, Ashur-Fabian O, Garfield D. Thyroid hormones and cancer: clinical studies of hypothyroidism in oncology. Curr Opin Endocrinol Diabetes Obes 2010, 17: 432–6.

    CAS  PubMed  Google Scholar 

  25. Piekielko-Witkowska A. Thyroid hormone receptors and cancer. Hot Thyroidology 2010, 1/10.

  26. Aranda A, Martínez-Iglesias O, Ruiz-Llorente L, García-Carpizo V, Zambrano A. Thyroid receptor: roles in cancer. Trends Endocrinol Metab 2009, 20: 318–24.

    CAS  PubMed  Google Scholar 

  27. Martinez MB, Ruan M, Fitzpatrick LA. Altered response to thyroid hormones by breast and ovarian cancer cells. Anticancer Res 2000, 20: 4141–6.

    CAS  PubMed  Google Scholar 

  28. Martinez MB, Ruan M, Fitzpatrick LA. Altered response to thyroid hormones by prostate and breast cancer cells. Cancer Chemother Pharmacol 2000, 45: 93–102.

    CAS  PubMed  Google Scholar 

  29. Hall LC, Salazar EP, Kane SR, Liu N. Effects of thyroid hormones on human breast cancer cell proliferation. J Steroid Biochem Mol Biol 2008, 109: 57–66.

    CAS  PubMed  Google Scholar 

  30. Cestari SH, Figueiredo NB, Conde SJ, et al. Influence of estradiol and triiodothyronine on breast cancer cell lines proliferation and expression of estrogen and thyroid hormone receptors. Arq Bras Endocrinol Metabol 2009, 53: 859–64.

    PubMed  Google Scholar 

  31. Dinda S, Sanchez A, Moudgil V. Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells. Oncogene 2002, 21: 761–8.

    CAS  PubMed  Google Scholar 

  32. González-Sancho JM, Figueroa A, López-Barahona M, López E, Beug H, Muñoz A. Inhibition of proliferation and expression of T1 and cyclin D1 genes by thyroid hormone in mammary epithelial cells. Mol Carcinog 2002, 34: 25–34.

    PubMed  Google Scholar 

  33. Hsieh ML, Juang HH. Cell growth effects of triiodothyronine and expression of thyroid hormone receptor in prostate carcinoma cells. J Androl 2005, 26: 422–8.

    CAS  PubMed  Google Scholar 

  34. Tsui KH, Hsieh WC, Lin MH, Chang PL, Juang HH. Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2. Prostate 2008, 68: 610–9.

    CAS  PubMed  Google Scholar 

  35. Poplawski P, Nauman A. Thyroid hormone — triiodothyronine — has contrary effect on proliferation of human proximal tubules cell line (HK2) and renal cancer cell lines (Caki-2, Caki-1) — role of E2F4, E2F5 and p107, p130. Thyroid Res 2008, 1: 5.

    PubMed Central  PubMed  Google Scholar 

  36. Murakami M, Araki O, Morimura T, et al. Expression of type II iodothyronine deiodinase in brain tumors. J Clin Endocrinol Metab 2000, 85: 4403–6.

    CAS  PubMed  Google Scholar 

  37. de Souza Meyer EL, Dora JM, Wagner MS, Maia AL. Decreased type 1 iodothyronine deiodinase expression might be an early and discrete event in thyroid cell dedifferentation towards papillary carcinoma. Clin Endocrinol (Oxf) 2005, 62: 672–8.

    Google Scholar 

  38. Huang Y, Prasad M, Lemon WJ, et al. Gene expression in papillary thyroid carcinoma reveals highly consistent profiles. Proc Natl Acad Sci U S A 2001, 98: 15044–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Ambroziak M, Pachucki J, Stachlewska-Nasfeter E, Nauman J, Nauman A. Disturbed expression of type 1 and type 2 iodothyronine deiodinase as well as titf1/nkx2-1 and pax-8 transcription factor genes in papillary thyroid cancer. Thyroid 2005, 15: 1137–46.

    CAS  PubMed  Google Scholar 

  40. Arnaldi LA, Borra RC, Maciel RM, Cerutti JM. Gene expression profiles reveal that DCN, DIO1, and DIO2 are underexpressed in benign and malignant thyroid tumors. Thyroid 2005, 15: 210–21.

    CAS  PubMed  Google Scholar 

  41. Murakami M, Araki O, Hosoi Y, et al. Expression and regulation of type II iodothyronine deiodinase in human thyroid gland. Endocrinology 2001, 142: 2961–7.

    CAS  PubMed  Google Scholar 

  42. Brtko J, Bobálová J, Podoba J, Schmutzler C, Köhrle J. Thyroid hormone receptors and type I iodothyronine 5′-deiodinase activity of human thyroid toxic adenomas and benign cold nodules. Exp Clin Endocrinol Diabetes 2002, 110: 166–70.

    CAS  PubMed  Google Scholar 

  43. Wawrzynska L, Sakowicz A, Rudzinski P, Langfort R, Kurzyna M. The conversion of thyroxine to triiodothyronine in the lung: comparison of activity of type I iodothyronine 5′ deiodinase in lung cancer with peripheral lung tissues. Monaldi Arch Chest Dis 2003, 59: 140–5.

    CAS  PubMed  Google Scholar 

  44. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000, 343: 185–9.

    CAS  PubMed  Google Scholar 

  45. Bessho K, Etani Y, Ichimori H, et al. Increased type 3 iodothyronine deiodinase activity in a regrown hepatic hemangioma with consumptive hypothyroidism. Eur J Pediatr 2010, 169: 215–21.

    CAS  PubMed  Google Scholar 

  46. Huang SA, Fish SA, Dorfman DM, et al. A 21-year-old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase. J Clin Endocrinol Metab 2002, 87: 4457–61.

    CAS  PubMed  Google Scholar 

  47. Sabatino L, Iervasi G, Ferrazzi P, Francesconi D, Chopra IJ. A study of iodothyronine 5′-monodeiodinase activities in normal and pathological tissues in man and their comparison with activities in rat tissues. Life Sci 2000, 68: 191–202.

    CAS  PubMed  Google Scholar 

  48. Pachucki J, Ambroziak M, Tanski Z, Luczak J, Nauman J, Nauman A. Type I 5′-iodothyronine deiodinase activity and mRNA are remarkably reduced in renal clear cell carcinoma. J Endocrinol Invest 2001, 24: 253–61.

    CAS  PubMed  Google Scholar 

  49. Master A, Wójcicka A, Piekiełko-Witkowska A, et al. Untranslated regions of thyroid hormone receptor beta 1 mRNA are impaired in human clear cell renal cell carcinoma. Biochim Biophys Acta 2010, 1802: 995–1005.

    CAS  PubMed  Google Scholar 

  50. Dentice M, Luongo C, Huang S, et al. Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci USA 2007, 104: 14466–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. LeBron BA, Pekary AE, Mirell C, Hahn TJ, Hershman JM. Thyroid hormone 5′-deiodinase activity, nuclear binding, and effects on mitogenesis in UMR-106 osteoblastic osteosarcoma cells. J Bone Miner Res 1989, 4: 173–8.

    CAS  PubMed  Google Scholar 

  52. Morimura T, Tsunekawa K, Kasahara T, et al. Expression of type 2 iodothyronine deiodinase in human osteoblast is stimulated bythyrotropin. Endocrinology 2005, 146: 2077–84.

    CAS  PubMed  Google Scholar 

  53. Calvo RM, Roda JM, Obregón MJ, Morreale de Escobar G. Thyroid hormones in human tumoral and normal nervous tissues. Brain Res 1998, 801: 150–7.

    CAS  PubMed  Google Scholar 

  54. Nauman P, Bonicki W, Michalik R, Warzecha A, Czernicki Z. The concentration of thyroid hormones and activities of iodothyronine deiodinases are altered in human brain gliomas. Folia Neuropathol 2004, 42: 67–73.

    CAS  PubMed  Google Scholar 

  55. Tannahill LA, Visser TJ, McCabe CJ, et al. Dysregulation of iodothyronine deiodinase enzyme expression and function in human pituitary tumours. Clin Endocrinol (Oxf) 2002, 56: 735–43.

    CAS  Google Scholar 

  56. Kim BW, Daniels GH, Harrison BJ, et al. Overexpression of type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels. J Clin Endocrinol Metab 2003, 88: 594–8.

    CAS  PubMed  Google Scholar 

  57. Meyer EL, Goemann IM, Dora JM, Wagner MS, Maia AL. Type 2 iodothyronine deiodinase is highly expressed in medullary thyroid carcinoma. Mol Cell Endocrinol 2008, 289: 16–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Debski MG, Pachucki J, Ambroziak M, Olszewski W, Bar-Andziak E. Human breast cancer tissue expresses high level of type 1 5′-deiodinase. Thyroid 2007, 17: 3–10.

    CAS  PubMed  Google Scholar 

  59. Rihn BH, Mohr S, McDowell SA, et al. Differential gene expression in mesothelioma. FEBS Lett 2000, 480: 95–100.

    CAS  PubMed  Google Scholar 

  60. Curcio C, Baqui MM, Salvatore D, et al. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J Biol Chem 2001, 276: 301 83–7.

    Google Scholar 

  61. Pinna G, Meinhold H, Hiedra L, et al. Elevated 3,5-diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors. J Clin Endocrinol Metab 1997, 82: 1535–42.

    CAS  PubMed  Google Scholar 

  62. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer 2008, 8: 743–54.

    CAS  PubMed  Google Scholar 

  63. Dentice M, Bandyopadhyay A, Gereben B, et al. The Hedgehoginducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol 2005, 7: 698–705.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Lupulescu A. Hormonal regulation of epidermal tumor development. J Invest Dermatol 1981, 77: 186–95.

    CAS  PubMed  Google Scholar 

  65. Huang SA. Deiodination and cellular proliferation: parallels between development, differentiation, tumorigenesis, and now regeneration. Endocrinology 2009, 150: 3–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Ruppe MD, Huang SA, Jan de Beur SM. Consumptive hypothyroidism caused by paraneoplastic production of type 3 iodothyronine deiodinase. Thyroid 2005, 15: 1369–72.

    CAS  PubMed  Google Scholar 

  67. Hassan MM, Kaseb A, Li D, et al. Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States. Hepatology 2009, 49: 1563–70.

    PubMed Central  PubMed  Google Scholar 

  68. Hellevik AI, Asvold BO, Bjøro T, Romundstad PR, Nilsen TI, Vatten LJ. Thyroid function and cancer risk: a prospective population study. Cancer Epidemiol Biomarkers Prev 2009, 18: 570–4.

    CAS  PubMed  Google Scholar 

  69. Cristofanilli M, Yamamura Y, Kau SW, et al. Thyroid hormone and breast carcinoma. Primary hypothyroidism is associated with a reduced incidence of primary breast carcinoma. Cancer 2005, 103: 1122–8.

    CAS  PubMed  Google Scholar 

  70. Tosovic A, Bondeson AG, Bondeson L, Ericsson UB, Malm J, Manjer J. Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 2010, 12: R33.

    PubMed Central  PubMed  Google Scholar 

  71. Bhargav PR, Mishra A, Agarwal G, Agarwal A, Verma AK, Mishra SK. Prevalence of hypothyroidism in benign breast disorders and effect of thyroxine replacement on the clinical outcome. World J Surg 2009, 33: 2087–93.

    PubMed  Google Scholar 

  72. Burke RE, McGuire WL. Nuclear thyroid hormone receptors in a human breast cancer cell line. Cancer Res 1978, 38: 3769–73.

    CAS  PubMed  Google Scholar 

  73. Bracke ME, Van Larebeke NA, Vyncke BM, Mareel MM. Retinoic acid modulates both invasion and plasma membrane ruffling of MCF-7 human mammary carcinoma cells in vitro. Br J Cancer 1991, 63: 867–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Martínez-Iglesias O, García-Silva S, Regadera J, Aranda A. Hypothyroidism enhances tumor invasiveness and metastasis development. PLoS One 2009, 4: e6428.

    PubMed Central  PubMed  Google Scholar 

  75. Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 2010, 15: 117–34.

    PubMed Central  PubMed  Google Scholar 

  76. Martínez-Iglesias O, Garcia-Silva S, Tenbaum SP, et al. Thyroid hormone receptor beta1 acts as a potent suppressor of tumor invasiveness and metastasis. Cancer Res 2009, 69: 501–9.

    PubMed  Google Scholar 

  77. Leonard JL. Non-genomic actions of thyroid hormone in brain development. Steroids 2008, 73: 1008–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Dentice M, Marsili A, Ambrosio R, et al. The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest 2010, 120: 4021–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Piehl S, Hoefig CS, Scanlan TS, Köhrle J. Thyronamines—Past, Present, and Future. Endocr Rev 2011, 32: 64–80.

    CAS  PubMed  Google Scholar 

  80. Lopez-Gines C, Cerda-Nicolas M, Gil-Benso R, et al. Association of loss of 1 p and alterations of chromosome 14 in meningioma progression. Cancer Genet Cytogenet 2004, 148: 123–8.

    CAS  PubMed  Google Scholar 

  81. Micci F, Haugom L, Ahlquist T, et al. Genomic aberrations in borderline ovarian tumors. J Transl Med 2010, 8: 21.

    PubMed Central  PubMed  Google Scholar 

  82. Bièche I, Khodja A, Lidereau R. Deletion mapping of chromosomal region 1p32-pter in primary breast cancer. Genes Chromosomes Cancer 1999, 24: 255–63.

    PubMed  Google Scholar 

  83. el-Rifai W, Tarmo L, Hemmer S, et al. DNA copy number losses at 1p32-pter in monozygotic twins concordant for breast cancer. Cancer Genet Cytogenet 1999, 112: 169–72.

    CAS  PubMed  Google Scholar 

  84. Opocher G, Schiavi F, Vettori A, et al. Fine analysis of the short arm of chromosome 1 in sporadic and familial pheochromocytoma. Clin Endocrinol (Oxf) 2003, 59: 707–15.

    CAS  Google Scholar 

  85. Menon AG, Rutter JL, von Sattel JP, et al. Frequent loss of chromosome 14 in atypical and malignant meningioma: identification of a putative ‘tumor progression’ locus. Oncogene 1997, 14: 611–6.

    CAS  PubMed  Google Scholar 

  86. Kim NR, Cho SJ, Suh YL. Allelic loss on chromosomes 1 p32, 9p21, 13q14, 16q22, 17p, and 22q12 in meningiomas associated with meningioangiomatosis and pure meningioangiomatosis. J Neurooncol 2009, 94: 425–30.

    CAS  PubMed  Google Scholar 

  87. Simon M, von Deimling A, Larson JJ, et al. Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res 1995, 55: 4696–701.

    CAS  PubMed  Google Scholar 

  88. Bello MJ, de Campos JM, Vaquero J, Kusak ME, Sarasa JL, Rey JA. High-resolution analysis of chromosome arm 1p alterations in meningioma. Cancer Genet Cytogenet 2000, 120: 30–6.

    CAS  PubMed  Google Scholar 

  89. Chang IB, Cho BM, Moon SM, Park SH, Oh SM, Cho SJ. Loss of heterozygosity at 1p, 7q, 17p, and 22q in meningiomas. J Korean Neurosurg Soc 2010, 48: 14–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Rajaram V, Brat DJ, Perry A. Anaplastic meningioma versus meningeal hemangiopericytoma: immunohistochemical and genetic markers. Hum Pathol 2004, 35: 1413–8.

    CAS  PubMed  Google Scholar 

  91. Mori K, Yoshida K, Kayama T, et al. Thyroxine 5-deiodinase in human brain tumors. J Clin Endocrinol Metab 1993, 77: 1198–202.

    CAS  PubMed  Google Scholar 

  92. Dichamp C, Taillibert S, Aguirre-Cruz L, et al. Loss of 14q chromosome in oligodendroglial and astrocytic tumors. J Neurooncol 2004, 67: 281–5.

    PubMed  Google Scholar 

  93. Sánchez-Franco F, Fernández L, Fernández G, Cacicedo L. Thyroid hormone action on ACTH secretion. Horm Metab Res 1989, 21: 550–2.

    PubMed  Google Scholar 

  94. Giustina A, Wehrenberg WB. Influence of thyroid hormones on the regulation of growth hormone secretion. European Journal of Endocrinology 1995, 133: 646–53.

    CAS  PubMed  Google Scholar 

  95. Barrera-Hernandez G, Soo Park K, Dace A, Zhan Q, Cheng S. Thyroid hormone-induced cell proliferation in GC cells is mediated by changes in G1 cyclin/cyclin-dependent kinase levels and activity. Endocrinology 1999, 140: 5267–74.

    CAS  PubMed  Google Scholar 

  96. Quintanar-Stephano A, Valverde C. Mitogenic effects of thyroxine and TRH on thyrotrophs and somatotrophs of the anterior pituitary gland in thyroidectomized rats. J Endocrinol 1997, 154: 149–53.

    CAS  PubMed  Google Scholar 

  97. Stahl JH, Kendall SK, Brinkmeier ML, et al. Thyroid hormone is essential for pituitary somatotropes and lactotropes. Endocrinology 1999, 140: 1884–92.

    CAS  PubMed  Google Scholar 

  98. Itagaki Y, Yoshida K, Ikeda H, et al. Thyroxine 5′-deiodinase in human anterior pituitary tumors. J Clin Endocrinol Metab 1990, 71: 340–4.

    CAS  PubMed  Google Scholar 

  99. Baur A, Buchfelder M, Köhrle J. Expression of 5′-deiodinase enzymes in normal pituitaries and in various human pituitary adenomas. Eur J Endocrinol 2002, 147: 263–8.

    CAS  PubMed  Google Scholar 

  100. Carr J, Bown NP, Case MC, Hall AG, Lunec J, Tweddle DA. High-resolution analysis of allelic imbalance in neuroblastoma cell lines by single nucleotide polymorphism arrays. Cancer Genet Cytogenet 2007, 172: 127–38.

    CAS  PubMed  Google Scholar 

  101. Hoshi M, Shiwaku HO, Hayashi Y, Kaneko Y, Horii A. Deletion mapping of 14q32 in human neuroblastoma defines an 1,100-kb region of common allelic loss. Med Pediatr Oncol 2000, 35: 522–5.

    CAS  PubMed  Google Scholar 

  102. Zhou Y, Ye H, Martin-Subero JI, et al. The pattern of genomic gains in salivary gland MALT lymphomas. Haematologica 2007, 92: 921–7.

    CAS  PubMed  Google Scholar 

  103. Rao PH, Roberts D, Zhao YJ, et al. Deletion of 1p32–p36 is the most frequent genetic change and poor prognostic marker in adenoid cystic carcinoma of the salivary glands. Clin Cancer Res 2008, 14: 5181–7.

    CAS  PubMed  Google Scholar 

  104. Kim TM, Yim SH, Lee JS, et al. Genome-wide screening of genomic alterations and their clinicopathologic implications in non-small cell lung cancers. Clin Cancer Res 2005, 11: 8235–42.

    CAS  PubMed  Google Scholar 

  105. Chizhikov V, Zborovskaya I, Laktionov K, et al. Two consistently deleted regions within chromosome 1p32-pterin human non-small cell lung cancer. Mol Carcinog 2001, 30: 151–8.

    CAS  PubMed  Google Scholar 

  106. Wiech T, Nikolopoulos E, Weis R, et al. Genome-wide analysis of genetic alterations in Barrett’s adenocarcinoma using single nucleotide polymorphism arrays. Lab Invest 2009, 89: 385–97.

    CAS  PubMed  Google Scholar 

  107. Ghadimi BM, Grade M, Mönkemeyer C, et al. Distinct chromosomal profiles in metastasizing and nonmetastasizing colorectal carcinomas. Cell Oncol 2006, 28: 273–81.

    CAS  PubMed  Google Scholar 

  108. Bando T, Kato Y, Ihara Y, Yamagishi F, Tsukada K, Isobe M. Loss of heterozygosity of 14q32 in colorectal carcinoma. Cancer Genet Cytogenet 1999, 111: 161–5.

    CAS  PubMed  Google Scholar 

  109. Al-Mulla F, AlFadhli S, Al-Hakim AH, Going JJ, Bitar MS. Metastatic recurrence of early-stage colorectal cancer is linked to loss of heterozygosity on chromosomes 4 and 14q. J Clin Pathol 2006, 59: 624–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Kim TM, Yim SH, Shin SH, et al. Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q. Int J Cancer 2008, 123: 2808–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Cazals-Hatem D, Rebouissou S, Bioulac-Sage P, et al. Clinical and molecular analysis of combined hepatocellular-cholangiocarcinomas. J Hepatol 2004, 41: 292–8.

    CAS  PubMed  Google Scholar 

  112. Qin LX, Tang ZY, Ye SL, et al. Chromosome 8p deletion is associated with metastasis of human hepatocellular carcinoma when high and low metastatic models are compared. J Cancer Res Clin Oncol 2001, 127: 482–8.

    CAS  PubMed  Google Scholar 

  113. Chen M, Ye Y, Yang H, et al. Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays. Int J Cancer 2009, 125: 2342–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Toma MI, Grosser M, Herr A, et al. Loss of heterozygosity and copy number abnormality in clear cell renal cell carcinoma discovered by high-density affymetrix 10K single nucleotide polymorphism mapping array. Neoplasia 2008, 10: 634–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Schullerus D, Herbers J, Chudek J, Kanamaru H, Kovacs G. Loss of heterozygosity at chromosomes 8p, 9p, and 14q is associated with stage and grade of non-papillary renal cell carcinomas. J Pathol 1997, 183: 151–5.

    CAS  PubMed  Google Scholar 

  116. Herbers J, Schullerus D, Müller H, et al. Significance of chromosome arm 14q loss in nonpapillary renal cell carcinomas. Genes Chromosomes Cancer 1997, 19: 29–35.

    CAS  PubMed  Google Scholar 

  117. Wang ZC, Lin M, Wei LJ, et al. Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers. Cancer Res 2004, 64: 64–71.

    CAS  PubMed  Google Scholar 

  118. Jung SH, Shin SH, Yim SH, Choi HS, Lee SH, Chung YJ. Integrated analysis of copy number alteration and RNA expression profiles of cancer using a high-resolution whole-genome oligonucleotide array. Exp Mol Med 2009, 41: 462–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Aarts M, Dannenberg H, deLeeuw RJ, et al. Microarray-based CGH of sporadic and syndrome-related pheochromocytomas using a 0.1–0.2 Mb bacterial artificial chromosome array spanning chromosome arm 1 p. Genes Chromosomes Cancer 2006, 45: 83–93.

    CAS  PubMed  Google Scholar 

  120. Roque L, Nunes VM, Ribeiro C, Martins C, Soares J. Karyotypic characterization of papillary thyroid carcinomas. Cancer 2001, 92: 2529–38.

    CAS  PubMed  Google Scholar 

  121. Hallor KH, Staaf J, Bovée JV, et al. Genomic profiling of chondrosarcoma: chromosomal patterns in central and peripheral tumors. Clin Cancer Res 2009, 15: 2685–94.

    CAS  PubMed  Google Scholar 

  122. Lindholm PM, Salmenkivi K, Vauhkonen H, et al. Gene copy number analysis in malignant pleural mesothelioma using oligonucleotide array CGH. Cytogenet Genome Res 2007, 119: 46–52.

    CAS  PubMed  Google Scholar 

  123. Flordal Thelander E, Ichimura K, Collins VP, et al. Detailed assessment of copy number alterations revealing homozygous deletions in 1 p and 13q in mantle cell lymphoma. Leuk Res 2007, 31: 1219–30.

    CAS  PubMed  Google Scholar 

  124. Espinet B, Salaverria I, Beà S, et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosomes Cancer 2010, 49: 439–51.

    CAS  PubMed  Google Scholar 

  125. Agueli C, Cammarata G, Salemi D, et al. 14q32/miRNA clusters loss of heterozygosity in acute lymphoblastic leukemia is associated with up-regulation of BCL11a. Am J Hematol 2010, 85: 575–8.

    CAS  PubMed  Google Scholar 

  126. Gittoes NJ, McCabe CJ, Verhaeg J, Sheppard MC, Franklyn JA. Thyroid hormone and estrogen receptor expression in normal pituitary and nonfunctioning tumors of the anterior pituitary. J Clin Endocrinol Metab 1997, 82: 1960–7.

    CAS  PubMed  Google Scholar 

  127. Fujarewicz K, Jarzab M, Eszlinger M, et al. A multi-gene approach to differentiate papillary thyroid carcinoma from benign lesions: gene selection using support vector machines with bootstrapping. Endocr Relat Cancer 2007, 14: 809–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Puzianowska-Kuznicka M, Krystyniak A, Madej A, Cheng SY, Nauman J. Functionally impaired TR mutants are present in thyroid papillary cancer. J Clin Endocrinol Metab 2002, 87: 1120–8.

    CAS  PubMed  Google Scholar 

  129. Schreck R, Schnieders F, Schmutzler C, Köhrle J. Retinoids stimulate type I iodothyronine 5′- deiodinase activity in human follicular thyroid carcinoma cell lines. J Clin Endocrinol Metab 1994, 79: 791–8.

    CAS  PubMed  Google Scholar 

  130. Hoftijzer HC, Liu YY, Morreau H, et al. Retinoic acid receptor and retinoid X receptor subtype expression for the differential diagnosis of thyroid neoplasms. Eur J Endocrinol 2009, 160: 631–8.

    CAS  PubMed  Google Scholar 

  131. Pasca di Magliano M, Di Lauro R, Zannini M. Pax8 has a key role in thyroid cell differentiation. Proc Natl Acad Sci U S A 2000, 97: 13144–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Friedrichsen S, Christ S, Heuer H, et al. Regulation of iodothyronine deiodinases in the Pax8-/- mouse model of congenital hypothyroidism. Endocrinology 2003, 144: 777–84.

    CAS  PubMed  Google Scholar 

  133. Miyauchi A, Takamura Y, Ito Y, et al. 3,5,3′-Triiodothyronine thyrotoxicosis due to increased conversion of administered levothyroxine in patients with massive metastatic follicular thyroid carcinoma. J Clin Endocrinol Metab 2008, 93: 2239–42.

    CAS  PubMed  Google Scholar 

  134. García-Solís P, Aceves C. 5′ Deiodinase in two breast cancer cell lines: effect of triiodothyronine, isoproterenol and retinoids. Mol Cell Endocrinol 2003, 201: 25–31.

    PubMed  Google Scholar 

  135. Toyoda N, Zavacki AM, Maia AL, Harney JW, Larsen PR. A novel retinoid X receptor-independent thyroid hormone response element is present in the human type 1 deiodinase gene. Mol Cell Biol 1995, 15: 5100–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Beech SG, Walker SW, Arthur JR, Lee D, Beckett GJ. Differential control of type-I iodothyronine deiodinase expression by the activation of the cyclic AMP and phosphoinositol signalling pathways in cultured human thyrocytes. J Mol Endocrinol 1995, 14: 171–7.

    CAS  PubMed  Google Scholar 

  137. Miller WR. Regulatory subunits of PKA and breast cancer. Ann NY Acad Sci 2002, 968: 37–48.

    CAS  PubMed  Google Scholar 

  138. Kwakkel J, Wiersinga WM, Boelen A. Differential involvement of nuclear factor-kappaB and activator protein-1 pathways in the interleukin-1 beta-mediated decrease of deiodinase type 1 and thyroid hormone receptor beta1 mRNA. J Endocrinol 2006, 189: 37–44.

    CAS  PubMed  Google Scholar 

  139. Jin L, Yuan RQ, Fuchs A, et al. Expression of interleukin-1 beta in human breast carcinoma. Cancer 1997, 80: 421–34.

    CAS  PubMed  Google Scholar 

  140. Pinto AE, Leite V, Soares J. Clinical implications of molecular markers in follicular cell-derived thyroid cancer. J Expert Rev Mol Diagn 2009, 9: 679–94.

    CAS  Google Scholar 

  141. Cengiz SE, Cetinkaya E, Altin S, et al. Nutritional and prognostic significance of sick euthyroid syndrome in non-small cell lung cancer patients. Intern Med 2008, 47: 211–6.

    PubMed  Google Scholar 

  142. Tanski Z. Low T3 Syndrome in patients suffering from renal cell clear carcinoma (RCC). The dependance on its diameter (T) and grading (G). Urologia Polska (Polish Journal of Urology) 2000, 53: 3.

    Google Scholar 

  143. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol 2010, 205: 1–13.

    CAS  PubMed  Google Scholar 

  144. Debaveye Y, Ellger B, Mebis L, Darras VM, Van den Berghe G. Regulation of tissue iodothyronine deiodinase activity in a model of prolonged critical illness. Thyroid 2008, 18: 551–60.

    CAS  PubMed  Google Scholar 

  145. Mebis L, Langouche L, Visser TJ, Van den Berghe G. The type II iodothyronine deiodinase is upregulated in skeletal muscle during prolonged critical illness. J Clin Endocrinol Metab 2007, 92: 3330–3.

    CAS  PubMed  Google Scholar 

  146. Gresner P, Gromadzinska J, Jablonska E, Kaczmarski J, Wasowicz W. Expression of selenoproteincoding genes SEPP1, SEP15 and hGPX1 in non-small cell lung cancer. Lung Cancer 2009, 65: 34–40.

    PubMed  Google Scholar 

  147. Ratnasinghe D, Tangrea JA, Andersen MR, et al. Glutathione peroxidase codon 198 polymorphism variant increases lung cancer risk. Cancer Res 2000, 60: 6381–3.

    CAS  PubMed  Google Scholar 

  148. Jablonska E, Gromadzinska J, Sobala W, Reszka E, Wasowicz W. Lung cancer risk associated with selenium status is modified in smoking individuals by Sep15 polymorphism. Eur J Nutr 2008, 47: 47–54.

    CAS  PubMed  Google Scholar 

  149. Rudd RM. Malignant mesothelioma. Br Med Bull 2010, 93: 105–23.

    CAS  PubMed  Google Scholar 

  150. Shukla A, Bosenberg MW, MacPherson MB, et al. Activated cAMP response element binding protein is overexpressed in human mesotheliomas and inhibits apoptosis. Am J Pathol 2009, 175: 2197–206.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Canettieri G, Celi FS, Baccheschi G, Salvatori L, Andreoli M, Centanni M. Isolation of human type 2 deiodinase gene promoter and characterization of a functional cyclic adenosine monophosphate response element. Endocrinology 2000, 141: 1804–13.

    CAS  PubMed  Google Scholar 

  152. Meyers RL. Tumors of the liver in children. Surg Oncol 2007, 16: 195–203.

    PubMed  Google Scholar 

  153. Kornasiewicz O, Debski M, Stepnowska M, Szałas A, Bar-Andziak E, Krawczyk M. The enzymatic activity of type 1 iodothyronine deiodinase (D1) is low in liver hemangioma: a preliminary study. Arch Immunol Ther Exp (Warsz) 2010, 58: 77–80.

    CAS  Google Scholar 

  154. Huang SA, Mulcahey MA, Crescenzi A, et al. Transforming growth factor-beta promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase. Mol Endocrinol 2005, 19: 3126–36.

    CAS  PubMed  Google Scholar 

  155. Ito N, Kawata S, Tsushima H, et al. Increased circulating transforming growth factor beta1 in a patient with giant hepatic hemangioma: possible contribution to an impaired immune function. Hepatology 1997, 25: 93–6.

    CAS  PubMed  Google Scholar 

  156. Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003, 88: 3202–11.

    CAS  PubMed  Google Scholar 

  157. Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Serum 3,3′,5′- triiodothyronine (rT3) and 3,5,3′-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005, 90: 4559–65.

    CAS  PubMed  Google Scholar 

  158. Simonides WS, Mulcahey MA, Redout EM, et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxicischemic disease in rats. J Clin Invest 2008, 118: 975–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Kester MH, Toussaint MJ, Punt CA, et al. Large induction of type III deiodinase expression after partial hepatectomy in the regenerating mouse and rat liver. Endocrinology 2009, 150: 540–5.

    CAS  PubMed  Google Scholar 

  160. Puzianowska-Kuznicka M, Nauman A, Madej A, Tanski Z, Cheng S, Nauman J. Expression of thyroid hormone receptors is disturbed in human renal clear cell carcinoma. Cancer Lett 2000, 155: 145–52.

    CAS  PubMed  Google Scholar 

  161. Kamiya Y, Puzianowska-Kuznicka M, McPhie P, Nauman J, Cheng SY, Nauman A. Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma. Carcinogenesis 2002, 23: 25–33.

    CAS  PubMed  Google Scholar 

  162. Rosen MD, Privalsky ML. Thyroid hormone receptor mutations found in renal clear cell carcinomas alter corepressor release and reveal helix 12 as key determinant of corepressor specificity. Mol Endocrinol 2009, 23: 1183–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Piekielko-Witkowska A, Wiszomirska H, Wojcicka A, et al. Disturbed expression of splicing factors in renal cancer affects alternative splicing of apoptosis regulators, oncogenes, and tumor suppressors. PLoS One 2010, 5: e13690.

    PubMed Central  PubMed  Google Scholar 

  164. Wu JX, Carpenter PM, Gresens C, et al. The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas. Oncogene 1990, 5: 989–1000.

    CAS  PubMed  Google Scholar 

  165. Franchi A, Calzolari A, Zampi G. Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton. Virchows Arch 1998, 432: 515–9.

    CAS  PubMed  Google Scholar 

  166. Gamberi G, Benassi MS, Bohling T, et al. C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression. Oncology 1998, 55: 556–63.

    CAS  PubMed  Google Scholar 

  167. Perez P, Schönthal A, Aranda A. Repression of c-fos gene expression by thyroid hormone and retinoic acid receptors. J Biol Chem 1993, 268: 23538–43.

    CAS  PubMed  Google Scholar 

  168. Pérez-Juste G, García-Silva S, Aranda A. An element in the region responsible for premature termination of transcription mediates repression of c-myc gene expression by thyroid hormone in neuroblastoma cells. J Biol Chem 2000, 275: 1307–14.

    PubMed  Google Scholar 

  169. Bellinger FP, Raman AV, Reeves MA, Berry MJ. Regulation and function of selenoproteins in human disease. Biochem J 2009, 422: 11–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Guigon CJ, Kim DW, Willingham MC, Cheng SY. Mutation of thyroid hormone receptor-β in mice predisposes to the development of mammary tumors. Oncogene 2011, 30: 3381–90.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Medical Centre of Postgraduate Education, ul. Marymoncka 99/103, 01-813, Warsaw, Poland

    A. Piekiełko-Witkowska PhD & A. Nauman

Authors
  1. A. Piekiełko-Witkowska PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Nauman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Piekiełko-Witkowska PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piekiełko-Witkowska, A., Nauman, A. Iodothyronine deiodinases and cancer. J Endocrinol Invest 34, 716–728 (2011). https://doi.org/10.3275/7754

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3275/7754

Key-words

Search

Navigation