Expression of SMAD proteins, TGF-beta/activin signaling mediators, in human thyroid tissues

Abstract

Objective: To investigate the expression of SMAD proteins in human thyroid tissues since the inactivation of TGF-β/activin signaling components is reported in several types of cancer. Phosphorylated SMAD 2 and SMAD3 (pSMAD2/3) associated with the SMAD4 induce the signal transduction generated by TGF-β and activin, while SMAD7 inhibits this intracellular signaling. Although TGF-β and activin exert antiproliferative roles in thyroid follicular cells, thyroid tumors express high levels of these proteins. Materials and methods: The protein expression of SMADs was evaluated in multinodular goiter, follicular adenoma, papillary and follicular carcinomas by immunohistochemistry. Results: The expression of pSMAD2/3, SMAD4 and SMAD7 was observed in both benign and malignant thyroid tumors. Although pSMAD2/3, SMAD4 and SMAD7 exhibited high cytoplasmic staining in carcinomas, the nuclear staining of pSMAD2/3 was not different between benign and malignant lesions. Conclusions: The finding of SMADs expression in thyroid cells and the presence of pSMAD2/3 and SMAD4 proteins in the nucleus of tumor cells indicates propagation of TGF-β/activin signaling. However, the high expression of the inhibitory SMAD7, mostly in malignant tumors, could contribute to the attenuation of the SMADs antiproliferative signaling in thyroid carcinomas. Arq Bras Endocrinol Metab. 2010;54(4):406-12 Keywords SMAD2/3; SMAD4; SMAD7; thyroid cancer; TGF-β; activin ResumoObjetivo: Investigar a expressão de proteínas SMAD em tecidos de tiroide humana desde que a inativação dos componentes da sinalização de TGF-β/activina é relatada em diversos tipos de câncer. SMAD 2 e SMAD3 fosforilados (pSMAD2/3) associados com SMAD4 induzem a transmissão do sinal gerado por TGF-β e activina, enquanto SMAD7 inibe essa sinalização intracelular. Embora TGF-β e activina exerçam efeitos antiproliferativos nas células foliculares da tiroide, tumores de tiroide expressam altos níveis dessas proteínas. Materiais e métodos: A expressão proteica de SMADs foi avaliada em bócio multinodular, adenoma folicular, carcinomas papilífero e folicular por imuno-histoquímica. Resultados: A expressão de pSMAD2/3, SMAD4 e SMAD7 foi observada tanto em tumores benignos como malignos da tiroide. Embora pSMAD2/3, SMAD4 e SMAD7 exibissem alta positividade citoplasmática em carcinomas, a positividade nuclear de pSMAD2/3 não foi diferente entre lesões benignas e malignas da tiroide. Conclusões: O achado da expressão de SMADs em células tiroidianas e a presença das proteínas pSMAD2/3 e SMAD4 no núcleo de células tumorais indicam propagação da sinalização TGF-β/activina. Contudo, a alta expressão de SMAD7 inibitório, principalmente em tumores malignos, poderia contribuir para atenuação da sinalização antiproliferativa de SMADs em carcinomas de tiroide. Arq Bras Endocrinol Metab. 2010;54(4):406-12 Descritores SMAD2/3; SMAD4; SMAD7; câncer de tiroide; TGF-β, activina

MicroRNA miR-146b-5p regulates signal transduction of TGF-β by repressing SMAD4 in thyroid cancer

“…In this context, elevated expression of miR-146b-5p could be a key factor in thyroid cancer progression, decreasing SMAD4 levels to overcome the TGF-b inhibitory signal. We have previously shown that SMAD4 may be present in thyroid tumors (Matsuo et al, 2010), suggesting that other factors may be involved in thyroid tumorigenesis. Because the overexpression of inhibitory SMAD7 (SMAD7) has been reported in thyroid tumor samples and cell lines (Cerutti et al, 2003;Matsuo et al, 2010), regulation of the TGF-b pathway by SMAD7 and other regulatory proteins may also take part in the refractoriness to the TGF-b signal by thyroid tumor cells.…”

“…We have previously shown that SMAD4 may be present in thyroid tumors (Matsuo et al, 2010), suggesting that other factors may be involved in thyroid tumorigenesis. Because the overexpression of inhibitory SMAD7 (SMAD7) has been reported in thyroid tumor samples and cell lines (Cerutti et al, 2003;Matsuo et al, 2010), regulation of the TGF-b pathway by SMAD7 and other regulatory proteins may also take part in the refractoriness to the TGF-b signal by thyroid tumor cells. Furthermore, crosstalk between the TGF-b signaling pathway and several other cancer-related pathways may contribute to the disruption of the TGF-b signal (Ellenrieder, 2008).…”

Disruption of transforming growth factor-β signaling in thyroid follicular epithelial cells or intrathyroidal fibroblasts does not promote thyroid carcinogenesis

“…Thus, some studies showed suppressive effect of TGF-β on thyroid cancer cell proliferation [15,16], whereas others resistance of thyroid cancers to TGF-β's anti-proliferative effect, at least partly due to miR-146b-5p mediated suppression of Smad4 expression [17], Smad4 mutations [18], elevated expression of Smad7 (an counterregulatory molecule of the canonical TGF-β signaling) [19], down-regulation of TβRII expression [20], etc. However, the recent studies showing overexpression of TGF-β in thyroid cancers of human and mouse origins [19,[21][22][23][24][25], particularly at their invasive fronts [22,23,25], strongly indicate involvement of TGF-β in invasion, metastasis and also epithelial-mesenchymal transition (EMT). From all these previous data as well as those with Tgfbr2 tpoKO mice in the current study, it can be concluded as follows; TGF-β does suppress proliferation of normal thyroid cells but is not strongly involved in tumor suppression by itself in the early carcinogenesis, and once thyroid cells transform, although some lose the responsiveness to TGF-β, TGF-β acts as a tumor promoter by promoting the aggressive phenotype (invasive and metastatic capabilities, and EMT phenotype) in the majority of thyroid cancers.…”

Prevalence of thyroid disorders and the correlation of thyroid profile with liver enzymes, serum activin-A and follistatin during the treatment of patients with chronic hepatitis C genotype 1 and 4

“…The expression of activins' intracellular mediators (Smad) have also been reported in thyroid cells and in the nucleus of thyroid tumour cells, indicating propagation of activin signalling in thyrocytes [16].…”