Increased type 3 deiodinase expression in papillary thyroid carcinoma.

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 ß1 (TGFß1). Interestingly, preincubation with mitogen-activated protein kinase (MAPK) cascade inhibitors U0126 (ERK pathway) and SB203580 (p38 pathway) decreased DIO3 mRNA levels and blocked the TGFß1-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.

Papel do fator de crescimento endotelial vascular nos carcinomas de tireóide / The role of vascular endothelial growth factor in tumor

O crescimento tumoral está diretamente relacionado com a neovascularização, a qual decorre do desequilíbrio entre os fatores pró-angiogênicos e antiangiogênicos, secretados pelas células neoplásicas. O fator de crescimento endotelial vascular (VEGF) desempenha papel chave na angiogênese tumoral, estimulando a proliferação, migração e sobrevivência das células endoteliais. Atua através da ligação a receptores tirosina quinase específicos: VEGFR-1/Flt-1, VEGFR-2/KDR e VEGFR-3. O aumento da expressão do VEGF e de seus receptores tem sido associado à progressão, metastatização e pior prognóstico em diversos tumores malignos. A compreensão das vias moleculares que envolvem o mecanismo de indução da angiogênese tumoral por fatores de crescimento como o VEGF aumentam as possibilidades de novas terapêuticas a serem utilizadas no tratamento de tumores malignos humanos. Evidências indicam um importante papel do VEGF nas neoplasias da tireóide e a utilização de inibidores do VEGF ou de seus receptores pode constituir um importante recurso terapêutico, já tendo sido utilizado em determinados tipos de tumores humanos. O presente artigo tem como objetivo fazer uma revisão da atuação do VEGF no crescimento tumoral com enfoque nas neoplasias malignas da tireóide.

The neoplasic process is directly related to neovascularization, an imbalance between pro-angiogenic and antiangiogenic factors. The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis, stimulating proliferation, migration and survival of endothelial cells. VEGF acts through binding to specific tyrosine kinase receptor: VEGFR-1/Flt-1, VEGFR-2/KDR and VEGFR-3. Increased expression of VEGF and its receptors have been associated with progression, metastasis and worse prognosis in human malignant tumors. Understanding molecular pathways of tumor angiogenesis related to growth factors such as VEGF is a crucial step on developing new treatment options. Evidence indicates an important role of VEGF in thyroid cancer and inhibition of VEGF or its receptors may constitute an important therapeutic resource, particularly for those patients with metastatic diseases. This aim of this article is to review the role of VEGF in tumor growth, focusing on thyroid malignancies.