Recovery of NIS expression in thyroid cancer cells by overexpression of Pax8 gene

Presta, Ivan; Arturi, Franco; Ferretti, Elisabetta; Mattei, Tiziana; Scarpelli, Daniela; Tosi, E; Scipioni, Angela; Celano, Marilena; Gulino, Alberto; Russo, Diego

doi:10.1186/1471-2407-5-80

Cited by 27 publications

(27 citation statements)

References 38 publications

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“…Earlier studies using either the TG or TPO promoter found that they were activated by TTF-1 and HNF3b/FoxA2 in thyroid carcinoma cell lines (Sato and Di Lauro, 1996;Ros et al, 1999;Shimura et al, 2001). In addition, Pax-8 leads to the re-expression of NIS, TPO, TG, and TTF-1 mRNAs in ARO cells (Presta et al, 2005). Our present study demonstrated that forced expression of either HNF3b/FoxA2 or TTF-1 was unable to induce differentiation of the thyroid cancer cells as measured by NIS mRNA expression and radioiodine uptake.…”

Section: Discussionmentioning

confidence: 60%

“…Thyroid transcription factor 1 is required for the development of the thyroid gland, and TTF-1-deficient mice lack a thyroid gland and die at birth (Kimura et al, 1996). The expression of Pax-8 and TTF-1 is low in thyroid carcinoma (Ros et al, 1999); and stable transfection with a Pax-8 expression vector in anaplastic thyroid carcinoma cell line, ARO, caused re-expression of endogenous NIS, TG, and TPO (Presta et al, 2005). Reporter gene analysis found that the promoter region of TG, TPO, and TSHR could be activated by the forced expression of either Pax-8 or TTF-1 in the papillary thyroid carcinoma cell line NPA (Ros et al, 1999).…”

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confidence: 99%

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Induction of sodium iodide symporter gene and molecular characterisation of HNF3β/FoxA2, TTF-1 and C/EBPβ in thyroid carcinoma cells

et al. 2008

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Thyroid carcinoma cells often do not express thyroid-specific genes including sodium iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (TG), and thyrotropin-stimulating hormone receptor (TSHR). Treatment of thyroid carcinoma cells (four papillary and two anaplastic cell lines) with histone deacetylase inhibitors (SAHA or VPA) modestly induced the expression of the NIS gene. The promoter regions of the thyroid-specific genes contained binding sites for hepatocyte nuclear factor 3 b (HNF3b)/forkhead box A2 (FoxA2), thyroid transcription factor 1 (TTF-1), and CCAAT/enhancer binding protein b (C/EBPb). Quantitative reverse transcription-polymerase chain reaction (RT -PCR) showed decreased expression of HNF3b/FoxA2 and TTF-1 mRNA in papillary thyroid carcinoma cell lines, when compared with normal thyroid cells. Forced expression of these genes in papillary thyroid carcinoma cells inhibited their growth. Furthermore, the CpG island in the promoter region of HNF3b/FoxA2 was aberrantly methylated; and treatment with 5-aza-2-deoxycytidine (5-Az) induced its expression. Immunohistochemical staining showed that C/EBPb was localised in the nucleus in normal thyroid cells but was detected in the cytoplasm in papillary thyroid carcinoma cells. Subcellular fractionation of papillary thyroid carcinoma cell lines also demonstrated high levels of expression of C/EBPb in the cytoplasm, suggesting that a large proportion of C/EBPb protein is inappropriately localised in the cytoplasm. In summary, these findings reveal novel abnormalities in thyroid carcinoma cells

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Section: Discussionmentioning

confidence: 60%

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confidence: 99%

Induction of sodium iodide symporter gene and molecular characterisation of HNF3β/FoxA2, TTF-1 and C/EBPβ in thyroid carcinoma cells

et al. 2008

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“…Otherwise, Presta et al 11 reported that Pax-8 activated the expression of NIS protein in a human thyroid anaplastic cancer cell line (ARO cells) and radioiodine uptake in ARO cells was partially restored by Pax-8. Schmitt et al 8 also found that Pax-8 had a moderate stimulating effect (threefold) on the NIS promoter in Hela and COS-7 cells and, comparatively, TTF-1 had no influence on the activation of NIS promoter.…”

Section: Discussionmentioning

confidence: 99%

“…10 Furthermore, Pax-8 could reactivate NIS, Pendrin, Tg, TPO and TTF-1 genes in the anaplastic thyroid carcinoma (ARO) cells and the ability to uptake radioiodine of ARO cells was partially restored. 11 We speculated that it might be a possible strategy for radioiodine therapy of tumor to promote iodide concentration in tumor cells by Pax-8 gene transduction. We therefore constructed an adenovirus vector (AdPax-8) for Pax-8 gene transfer to induce reactivation of endogenous thyroid-specific genes.…”

Section: Introductionmentioning

confidence: 99%

Radioiodine therapy of thyroid carcinoma following Pax-8 gene transfer

Huang

et al. 2011

Gene Ther

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The thyroid transcription factor Pax-8 could bind with the promoter/enhancer of thyroid-specific genes such as thyroglobulin (Tg), thyroperoxidase (TPO) and sodium iodide symporter (NIS), and regulate the expression of these proteins in thyrocyte. Promoting iodide accumulation in tumor cells by re-expression of Pax-8 provides a possible strategy for radioiodine therapy of tumor. Therefore, we investigated the effect of Pax-8 gene transfer on radioiodine therapy of thyroid carcinoma. The human Pax-8 gene was transfected into the human thyroid carcinoma (K1 and F133) cells by the recombinant adenovirus vector. Although the NIS mRNA was not detected, the expression of mRNA and proteins of Tg and TPO in AdPax-8-infected F133 cells were activated by Pax-8. Iodide uptake in thyroid carcinoma cells was reactivated by Pax-8 (increasing 3.3-fold in K1 cells and 5.7-fold in F133 cells). Moreover, Pax-8 promoted iodide organification and the retention time of iodine in Pax-8-expressing cells apparently prolonged in vitro and in vivo (Po0.05). Pax-8-expressing thyroid carcinoma cells were selectively killed by radioiodine. The AdPax-8-infected tumors in vivo clearly visualized in scanning images at 12 h after administration of radioiodine. These results indicate that Pax-8 can promote iodide uptake, and specifically prolong the retention time of iodide in thyroid cancer in vitro and in vivo by promoting the expression of TPO and Tg proteins. Pax-8 gene transfection may lead to effective radioiodine therapy of tumor.

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“…Reexpression of Pax8 is associated with the recovery of NIS, as well as TPO and Tg mRNA expressions in a rat thyroid cell line (77). Presta et al (78) showed that stably transfection of Pax8 into thyroid tumor cells recovers their iodine uptake ability.…”

Section: Other Factorsmentioning

confidence: 99%

The importance of sodium/iodide symporter (NIS) for thyroid cancer management

Carvalho

Ferreira

2007

Arq Bras Endocrinol Metab

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The thyroid gland has the ability to uptake and concentrate iodide, which is a fundamental step in thyroid hormone biosynthesis. Radioiodine has been used as a diagnostic and therapeutic tool for several years. However, the studies related to the mechanisms of iodide transport were only possible after the cloning of the gene that encodes the sodium/iodide symporter (NIS). The studies about the regulation of NIS expression and the possibility of gene therapy with the aim of transferring NIS gene to cells that normally do not express the symporter have also become possible. In the majority of hypofunctioning thyroid nodules, both benign and malignant, NIS gene expression is maintained, but NIS protein is retained in the intracellular compartment. The expression of NIS in non-thyroid tumoral cells in vivo has been possible through the transfer of NIS gene under the control of tissue-specific promoters. Apart from its therapeutic use, NIS has also been used for the localization of metastases by scintigraphy or PET-scan with 124 I. In conclusion, NIS gene cloning led to an important development in the field of thyroid pathophysiology, and has also been fundamental to extend the use of radioiodine for the management of non-thyroid tumors. A glândula tireóide tem capacidade de captar e concentrar iodeto, etapa fundamental na biossíntese dos hormônios tireóideos. O uso de iodo radioativo para fins de diagnóstico e terapia das doenças da tireóide vem sendo feito há muitos anos. Entretanto, somente após a clonagem do gene que codifica o cotransportador de sódio/iodeto (NIS) houve aumento significativo dos estudos relacionados ao mecanismo de transporte de iodeto. Os estudos sobre a regulação da expressão do NIS e a possibilidade de terapia gênica visando à transferência do gene NIS para células que normalmente não expressam esse transportador, foram também viabilizados. Na maior parte dos nódulos tireóideos hipofuncionantes, tanto benignos quanto malignos, a expressão do gene do NIS está presente, mas a proteína NIS fica retida no compartimento intracelular. A transferência do gene usando-se promotores tecido-específicos possibilitou a expressão do NIS em células tumorais não-tireóideas in vivo. Além do seu uso terapêutico, o NIS também vem sendo usado para a localização de metástases tumorais através da cintilografia ou do PET-scan usando-se 124 I. Em conclusão, a clonagem do NIS possibilitou enorme avanço na área de fisiopatologia tireóidea e foi também fundamental para estender o uso do radioiodo para tumores não tireóideos.

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Recovery of NIS expression in thyroid cancer cells by overexpression of Pax8 gene

Cited by 27 publications

References 38 publications

Induction of sodium iodide symporter gene and molecular characterisation of HNF3β/FoxA2, TTF-1 and C/EBPβ in thyroid carcinoma cells

Induction of sodium iodide symporter gene and molecular characterisation of HNF3β/FoxA2, TTF-1 and C/EBPβ in thyroid carcinoma cells

Radioiodine therapy of thyroid carcinoma following Pax-8 gene transfer

The importance of sodium/iodide symporter (NIS) for thyroid cancer management

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