Differential regulation of sodium/iodide symporter NIS gene promoter by p53, p63 and p73 in human cholangiocarcinoma (CCA) and hepatocellular (HCC) cell lines

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 124I. 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.

Download Full-text

A GC Box in the Human Sodium Iodide Symporter Gene Promoter is Essential for Full Activity

Thyroid ◽

10.1089/105072502753522338 ◽

2002 ◽

Vol 12 (2) ◽

pp. 107-114 ◽

Cited By ~ 6

Author(s):

Jimin Xu ◽

Takahiko Kogai ◽

Gregory A. Brent ◽

Jerome M. Hershman

Keyword(s):

Sodium Iodide ◽

Gene Promoter ◽

Sodium Iodide Symporter ◽

Full Activity ◽

Gc Box

Download Full-text

Application of 188Rhenium as an Alternative Radionuclide for Treatment of Prostate Cancer after Tumor-Specific Sodium Iodide Symporter Gene Expression

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-0402 ◽

2007 ◽

Vol 92 (11) ◽

pp. 4451-4458 ◽

Cited By ~ 37

Author(s):

Michael J. Willhauck ◽

Bibi-Rana Sharif Samani ◽

Franz-Josef Gildehaus ◽

Ingo Wolf ◽

Reingard Senekowitsch-Schmidtke ◽

...

Keyword(s):

Prostate Cancer ◽

Prostate Specific Antigen ◽

Therapeutic Effect ◽

Half Life ◽

Sodium Iodide ◽

Specific Antigen ◽

Volume Reduction ◽

Sodium Iodide Symporter ◽

Nis Gene

Abstract Context: We reported recently the induction of iodide accumulation in prostate cancer cells (LNCaP) by prostate-specific antigen promoter-directed sodium iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131iodine (131I). These data demonstrated the potential of the NIS gene as a novel therapeutic gene, although in some extrathyroidal tumors, therapeutic efficacy may be limited by rapid iodide efflux due to a lack of iodide organification. Objective: In the current study, we therefore studied the potential of 188rhenium (188Re), as an alternative radionuclide, also transported by NIS, with a shorter half-life and higher energy β-particles than 131I. Results: NIS-transfected LNCaP cells (NP-1) concentrated 8% of the total applied activity of 188Re as compared with 16% of 125I, which was sufficient for a therapeutic effect in an in vitro clonogenic assay. γ-Camera imaging of NP-1 cell xenografts in nude mice revealed accumulation of 8–16% injected dose (ID)/g 188Re (biological half-life 12.9 h), which resulted in a 4.7-fold increased tumor absorbed dose (450 mGy/MBq) for 188Re as compared with 131I. After application of 55.5 MBq 131I or 188Re, smaller tumors showed a similar average volume reduction of 86%, whereas in larger tumors volume reduction was significantly increased from 73% after 131I treatment to 85% after application of 188Re. Conclusion: Although in smaller prostate cancer xenografts both radionuclides seemed to be equally effective after prostate-specific antigen promoter-mediated NIS gene delivery, a superior therapeutic effect has been demonstrated for 188Re in larger tumors.

Download Full-text

Telomerase-Driven Expression of the Sodium Iodide Symporter (NIS) for in Vivo Radioiodide Treatment of Cancer: A New Broad-Spectrum NIS-Mediated Antitumor Approach

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2010-2373 ◽

2011 ◽

Vol 96 (9) ◽

pp. E1435-E1443 ◽

Cited By ~ 16

Author(s):

Garcilaso Riesco-Eizaguirre ◽

Antonio De la Vieja ◽

Irene Rodríguez ◽

Soledad Miranda ◽

Pilar Martín-Duque ◽

...

Keyword(s):

Therapeutic Effect ◽

Cell Lines ◽

Sodium Iodide ◽

Human Cancer ◽

131I Therapy ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Tumor Xenografts ◽

Human Cancer Cell Lines

Abstract Context: Telomerase promoters (hTERT and hTR) are useful for transcriptional targeting in gene therapy models of cancer. Telomerase-driven expression of the sodium iodide symporter (NIS) in tumor cells has been successfully used as a reporter gene in vivo using positron emission tomography (PET) imaging. Objective: The aim of this study was to investigate the NIS-mediated therapeutic effect of telomerase promoters in a wide variety of human cancer cell lines. Design and Methods: Promoter fragments from either hTERT or hTR were used to drive the expression of NIS in cell lines derived from melanoma (M14), breast (MDA-MB-231), colon (HT-29), lung (H460), ovarian (OVCAR-3), and thyroid (TPC-1) carcinomas. Iodide uptake assays, protein immunodetection, and clonigenic assays were used to confirm NIS functional expression and the 131I-mediated cytopathic effect. Tumor xenografts in mice were infected with hTERT and hTR and then treated using radioiodide. Results: Both promoters were selectively active in cancer cells that were effectively killed by exposure to 131I. One single dose of 1 mCi 131I markedly suppressed tumor growth of melanoma-derived tumor xenografts compared with controls. This effect was more modest in colon cancer-derived xenografts in part due to the reduced infectivity and the tumor cystic nature. The therapeutic effect of hTR promoter was found to be stronger than that of hTERT promoter. Conclusions: These results demonstrate that telomerase-driven expression of NIS could potentially have applications for 131I therapy of a wide variety of cancers. Additionally, this is the first study to report NIS-mediated 131I therapy of melanoma tumors in vivo.

Download Full-text

Differential regulation of apical and basal iodide transporters in the thyroid by thyroglobulin

Journal of Endocrinology ◽

10.1677/joe.1.06677 ◽

2006 ◽

Vol 189 (2) ◽

pp. 247-255 ◽

Cited By ~ 47

Author(s):

Koichi Suzuki ◽

Leonard D Kohn

Keyword(s):

Gene Expression ◽

Exposure Time ◽

Sodium Iodide ◽

Present Report ◽

Differential Regulation ◽

Specific Gene ◽

Special Focus ◽

Sodium Iodide Symporter ◽

Pendred Syndrome ◽

Pds Gene

We have shown that thyroglobulin (Tg) is a potent autocrine regulator of thyroid-specific gene expression, and proposed that the accumulated follicular Tg within the colloid is a major factor in determining follicular function. In the present report, we examined the effect of Tg on the action of TSH/cAMP and iodine with special focus on the regulation of basolateral and apical iodide transporters; the sodium/iodide symporter (NIS) and the pendred syndrome gene (PDS) by Tg. We show that expression of NIS and PDS are differentially regulated by Tg concentration and exposure time. In addition, we found that PDS gene was induced by TSH/cAMP and iodide in the presence of Tg. Based on these results, we propose a model for the physiological turnover of follicular function that is dynamically regulated by Tg.

Download Full-text