title: Increased type 3 deiodinase expression in papillary thyroid carcinoma.
abstract: BACKGROUND
  Thyroid hormone regulates a wide range of cellular activities, including the balance between cell proliferation and differentiation. The thyroid-hormone-inactivating type 3 deiodinase (DIO3, D3) has been shown to be reactivated in human neoplasias. Here, we evaluated DIO3 expression in human papillary thyroid carcinoma (PTC).
  
  
  METHODS
  Tumor and surrounding normal thyroid tissue were collected from 26 unselected patients with PTC. Clinical data were retrospectively reviewed in medical records. DIO3 mRNA levels were measured by real-time polymerase chain reaction and D3 activity by paper-descendent chromatography. Studies of DIO3 gene regulation were performed in a human PTC-derived cell line (K1 cells). BRAF(V600E) mutation was identified in DNA from paraffin-embedded tissues by direct sequencing. Immunohistochemistry analyses were performed using a specific human D3 antibody.
  
  
  RESULTS
  Increased D3 activity was detected in all 26 PTC samples analyzed as compared with adjacent thyroid tissue. The augmentations in D3 activity were paralleled by increased DIO3 mRNA levels (approximately fivefold). In PTC-derived cells, DIO3 transcripts were further upregulated by the transforming growth factor β1 (TGFβ1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased DIO3 mRNA levels and blocked the TGFβ1-induced increase in DIO3 transcripts, suggesting that D3 induction might be mediated through the MAPK signaling pathway. Accordingly, DIO3 mRNA and activity levels were significantly higher in BRAF(V600E)-mutated samples (p=0.001). Increased D3 activity was correlated with tumor size (r=0.68, p=0.003), and associated with lymph node (p=0.03) or distant metastasis (p=0.006) at diagnosis. Conversely, decreased levels of the thyroid-hormone-activating type 2 deiodinase (DIO2) gene were observed in PTC, which might contribute to further decreases in intracellular thyroid hormone levels. Increased D3 expression was also observed in follicular thyroid carcinoma but not in medullary or anaplastic thyroid carcinoma samples.
  
  
  CONCLUSIONS
  These results indicate that the malignant transformation of thyroid follicular cell toward PTC promotes opposite changes in DIO3 and DIO2 expression by pretranscriptional mechanisms. The association between increased levels of D3 activity and advanced disease further supports a role for intracellular triiodothyronine concentration on the thyroid tumor cell proliferation or/and dedifferentiation.
authors: Thyroid Section, Endocrine Division, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2350, Porto Alegre, RS, Brazil.
authors: Mírian
authors: M
authors: Romitti
authors: Simone Magagnin
authors: SM
authors: Wajner
authors: Nadja
authors: N
authors: Zennig
authors: Iuri Martin
authors: IM
authors: Goemann
authors: Ana Laura
authors: AL
authors: Bueno
authors: Erika L Souza
authors: EL
authors: Meyer
authors: Ana Luiza
authors: AL
authors: Maia
mesh_terms: D000328:Adult; D002070:Butadienes / Q000494:pharmacology; D002277:Carcinoma / Q000201:enzymology*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002648:Child; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007453:Iodide Peroxidase / Q000032:analysis / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012189:Retrospective Studies; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000201:enzymology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D053773:Transforming Growth Factor beta1; C113580:U 0126; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C093642:SB 203580