Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Eletroencefalografia/métodos , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/cirurgia , Monitorização Neurofisiológica Intraoperatória/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Pré-Escolar , Eletroencefalografia/normas , Humanos , Complicações Intraoperatórias/diagnóstico , Complicações Intraoperatórias/fisiopatologia , Monitorização Neurofisiológica Intraoperatória/normas , Masculino , Espectroscopia de Luz Próxima ao Infravermelho/normasRESUMO
BACKGROUND: In the thyroid, iodine deficiency (ID) induces angiogenesis via a tightly controlled reactive oxygen species (ROS)-hypoxia inducible factor-1 (HIF-1)-vascular endothelial growth factor (VEGF) dependent pathway (ROS-HIF-VEGF). Deficient iodine intake may be associated with increased thyroid cancer incidence. The hypothesis of this work is to test whether ID affects the angiogenic processes in thyroid malignant cells by altering the ROS-HIF-VEGF pathway. METHODS: Goiters were obtained in RET/PTC3 transgenic and wild-type (wt) mice and ID was induced in three thyroid carcinoma cell lines (TPC-1, 8305c, and R082-w1). Thyroid blood flow, VEGF mRNA and protein, and HIF-1α protein expression were measured. The role of HIF-1 and of ROS was assessed using echinomycin and N-acetylcysteine (NAC), respectively. RESULTS: The goitrogen treatment increased the thyroid blood flow in wt and RET/PTC3 mice. Compared with wt mice, basal VEGF expression was higher in RET/PTC3 mice and increased with goitrogen treatment. In the three cell lines, ID induced marked increases in VEGF mRNA, and moderate increases in HIF-1α protein expression that were not transient as in normal cells. ID-induced VEGF mRNA expression was fully (8305c), partially (TPC-1), or not (R082-w1) blocked by echinomycin. NAC had no effect on ID-induced VEGF mRNA and HIF-1α protein expression in the three cell lines. CONCLUSIONS: ID induces a long lasting angiogenic phenotype in thyroid cancer cells that occurs through VEGF induction via a pathway partially mediated by HIF-1, but not by ROS. These results suggest that, in contrast with normal cells, ID-induced angiogenesis in cancer cells occurs via alternative and likely less controlled routes, thereby leading to uncontrolled growth.
Assuntos
Carcinoma/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Iodo/deficiência , Neoplasias da Glândula Tireoide/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Carcinoma/irrigação sanguínea , Linhagem Celular Tumoral , Deficiências Nutricionais/complicações , Deficiências Nutricionais/metabolismo , Humanos , Fluxometria por Laser-Doppler , Camundongos , Camundongos Transgênicos , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , RNA Mensageiro/análise , Espécies Reativas de Oxigênio/metabolismo , Simportadores/metabolismo , Glândula Tireoide/irrigação sanguínea , Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/irrigação sanguínea , Neoplasias da Glândula Tireoide/diagnóstico por imagem , UltrassonografiaRESUMO
Goiter is associated with increased oxidative stress (OS). We studied the effects of an anti-inflammatory agent, 15 deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) and an antioxidant, N-acetylcysteine (NAC), on OS, thyroid function, and goiter expansion in a model of goiter induced by propylthiouracil (PTU) or perchlorate. OS was assessed by the immunodetection of 4-hydroxynonenal, thyroid function by measuring thyroxin (T4) and thyrotropin (TSH) plasma levels and detecting T4-rich thyroglobulin (Tg-I), and goiter expansion by weighing the thyroids and measuring cell proliferation (PCNA and cyclin D1 immunodetection). In both PTU and perchlorate-induced goiters, OS, TSH plasma levels, thyroid weight, and cell proliferation were strongly enhanced, whereas Tg-I expression was negative. All these parameters were reversed by NAC and 15dPGJ2 in PTU-goiters. In perchlorate-goiters, TSH plasma levels remained elevated and Tg-I-negative after NAC or 15dPGJ2 treatment. OS was reduced by NAC, but not by 15dPGJ2. In addition, NAC reduced PCNA and cyclin D1 immunostainings, as well as thyroid weight, whereas 15dPGJ2 influenced neither thyroid weight nor cell proliferation. In conclusion, NAC and 15dPGJ2 overcome PTU- but not perchlorate-induced effects. The retrieval of hormonal synthesis may result from direct chemical interactions between PTU and NAC/15dPGJ2. Although 15dPGJ2 has no effect in perchlorate-goiters, the reduction of OS by NAC is associated with altered goiter development, making OS a required condition for the growth of the thyroid gland.