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Endocrinology Vol. 145, No. 3 1290-1293
Copyright © 2004 by The Endocrine Society

Transcriptional Regulation of Human Sodium/Iodide Symporter Gene: A Role for Redox Factor-1

Cinzia Puppin, Franco Arturi, Elisabetta Ferretti, Diego Russo, Rosario Sacco, Gianluca Tell, Giuseppe Damante and Sebastiano Filetti

Dipartimento di Scienze e Tecnologie Biomediche (C.P., G.T., G.D.), University of Udine, 33100 Udine, Italy; Dipartimento di Medicina Sperimentale e Clinica "G. Salvatore" and Dipartimento di Scienze Farmacobiologiche, University of Catanzaro (F.A., D.R., R.S.), 88100 Catanzaro, Italy; and Dipartimento di Scienze Cliniche and Dipartimento di Medicina Sperimentale e Patologia (E.F., S.F.), University of Rome "La Sapienza," 00161 Rome, Italy

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Dipartimento di Scienze Cliniche-Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico, 155, 00161 Roma, Italy. E-mail: sebastiano.filetti{at}uniroma1.it.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The transcriptional regulation of the human sodium/iodide symporter (NIS) gene in normal and transformed thyroid cells is a crucial issue in attempting to restore iodide uptake and use radioiodine as a therapeutic treatment of thyroid cancer. Previous investigations have shown that the multifunctional protein apurinic apyrimidinic endonuclease/redox factor 1 (APE/Ref-1) plays an important role in regulation of thyroid-specific gene transcription. In this study, we investigated the effects of APE/Ref-1 on human NIS promoter activity. Cotransfection experiments performed in nonthyroid HeLa cells demonstrated that APE/Ref-1 exerts both PAX8-dependent and PAX8-independent effects. In fact, in the absence of PAX8, overexpression of APE/Ref-1 enhanced NIS promoter activity 2-fold. When the expression plasmid of APE/Ref-1 was transfected together with an expression plasmid for PAX8, a strong cooperative effect was detected with an increase of NIS promoter activity 9-fold over control. The PAX8-independent effect of APE/Ref-1 was specific for the NIS promoter, resulting not present for the promoter of the thyroperoxidase (TPO) gene. It was, at least in part, due to the up-regulation of the transcriptional activity of the ubiquitous factor early growth response-1 (Egr-1). In the thyroid tumor cell lines TPC-1 and B-CPAP, APE/Ref-1 was not effective by itself, and it also failed to increase PAX8 stimulation on NIS promoter activity. These data demonstrate a role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. However, restoring the PAX8-APE/Ref-1 expression in tumor cells may not be sufficient to obtain adequate levels of NIS gene expression.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
THE ABILITY OF thyroid cells to concentrate radioiodine is largely exploited in the diagnosis of nodular lesions as well as the treatment of recurrent and metastatic thyroid cancer. Unfortunately, a number of thyroid carcinomas have lost this capacity (1), mainly for a defective function or expression of the sodium/iodide symporter (NIS) (2, 3, 4, 5). Thus, recovery of NIS function in transformed thyrocytes is crucial to make them eligible for an effective radioiodine treatment of cancer disease. For this purpose, two NIS-based therapeutic approaches are currently explored: the first approach includes the delivery, by an appropriate viral vector, of the NIS gene driven by a strong viral promoter to thyroid tumor cells; the second approach is based on attempts to stimulate the endogenous NIS expression by acting on the molecular mechanisms underlying its transcriptional regulation. The latter approach may take advantage of the characterization of the human NIS promoter region (6, 7, 8, 9, 10, 11, 12, 13, 14). Several transcriptional regulators control NIS promoter activity. A leading role is exerted by PAX8 (9), which, in turn, is controlled by apurinic apyrimidinic endonuclease/redox factor 1 (APE/Ref-1), a multifunctional protein provided of endonuclease and redox activity (15, 16). However, no data have been produced so far about a role for APE/Ref-1 in the regulation of NIS promoter activity. In this study, we demonstrated that APE/Ref-1 stimulates the activity of NIS promoter, both by itself and through influencing PAX8 activity, but this pathway is not functioning in thyroid tumor cells.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Expression vectors, promoters, and reporter genes
The NIS promoter activity was investigated by using a clone, kindly provided by Dr. U. Loos (University of Ulm, Ulm, Germany), containing 2.4 kb of 5' genomic sequence for the NIS promoter, containing the minimal promoter linked to the luciferase (LUC) gene as reporter (6, 7). The thyroperoxidase (TPO) promoter activity was measured by using the construct described previously (17). The efficiency of transfection was normalized by using a construct containing either the Rous sarcoma virus (RSV) promoter linked to the chloramphenicol-acetyl-transferase (CAT) gene or the cytomegalovirus (CMV) promoter linked to the LUC gene. Expression vectors for PAX8 and Ref-1 are described by Tell et al. (16). Expression vector of early growth response-1 (Egr-1) is described by Huang et al. (18).

Cell culture and transfection assays
HeLa cells were obtained by American Type Culture Collection (Manassas, VA) and cultured in DMEM with 10% of calf serum (Life Technologies, Inc., Invitrogen Ltd., Paisley, UK). FRTL-5 rat thyroid cells were grown in Coon’s modified Ham F12 medium supplemented with 5% calf serum and a six-hormone mixture as described (19). TPC-1 and B-CPAP cell lines derived from human papillary thyroid cancer (20) were cultured in DMEM supplemented with 10% fetal bovine serum.

The calcium phosphate coprecipitation method used for transfections was performed as described elsewhere (17). HeLa, TPC-1, and B-CPAP cells were plated at 6 x 105 cells per 100-mm culture dish 20 h before transfection. FRTL-5 cells were plated at 1.5 x 106 cells per 100-mm culture dish 48 h before transfection and 3 h before the addition of the DNA calcium phosphate precipitates; the medium was changed to DMEM containing 5% calf serum and growth factors. Plasmids were used in the following amounts per dish: CMV-LUC, 2 µg; RSV-CAT, 2 µg; pNIS-LUC, 7 µg; PAX8 expression vector, 0.5 µg; APE/Ref-1 expression vector, 2 µg; and Egr-1 expression vector, 2 µg. Cells were harvested 44 h after transfection, and cell extracts were prepared by a standard freeze-and-thaw procedure. CAT protein was measured by an ELISA method (Amersham Pharmacia Biotech, Milan, Italy). LUC activity was measured by a chemiluminescence procedure (16).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Elucidation of the factors involved in the regulation of the human NIS promoter activity may provide useful information to establish a treatment able to restore the iodide uptake in thyroid cancer cells by means of recovering the endogenous NIS gene expression. Previous data indicate that the multifunctional protein APE/Ref-1 plays a role in regulating thyroid-specific transcription (16). In addition, it is expressed in thyroid cells under the regulation of TSH and shows a reduced nuclear expression in both thyroid tumor tissues and cell lines (21, 22). Thus, we investigated the role of APE/Ref-1 in the control of the NIS promoter.

In the first set of experiments, we tested the effects of the overexpression of APE/Ref-1 on NIS promoter activity. Cotransfection of HeLa cells with pNIS-LUC and a APE/Ref-1 expression vector determined a 2-fold increase in the NIS promoter (Fig. 1Go). This activating effect was specific; in fact, it was not detected when the effect of APE/Ref-1 overexpression was assayed on the TPO promoter (Fig. 1Go). Interestingly, in HeLa cells, the NIS promoter exhibited a basal activity higher than that of the TPO promoter (Fig. 1Go). These data are in agreement with the reported extrathyroidal gene expression of the NIS promoter (Refs. 2, 3, 4, 5 and our unpublished observations).



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  		FIG. 1. Effect of APE/Ref-1 on transcriptional activity of NIS and TPO promoters. Transfections were performed in HeLa cells as described in Materials and Methods. Transcriptional activity was normalized for transfection efficiency by using the RSV-CAT construct. Each bar represents the mean value ± SD of four independent transfection experiments. P value was calculated by the Student’s t test.

 
Because APE/Ref-1 is known to activate the PAX8 DNA binding activity and its transcriptional function (16), we tested whether cooperation of these two factors occurred in the regulation of NIS promoter activity. Figure 2Go shows that expression of APE/Ref-1 potentiated PAX8 effects on HeLa cells with a 9-fold increase of the effects over control. Conversely, TPO promoter activity, which is responsive to PAX8, was only weakly influenced by coexpression of PAX8 and APE/Ref-1, confirming the peculiar regulation of NIS gene transcription, as already observed in vivo in thyroid tissues (23). In addition, the finding that APE/Ref-1 up-regulated NIS promoter also in the absence of PAX8 indicates that, in this case, the APE/Ref-1 up-regulation was due also to PAX8-independent mechanisms.



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  		FIG. 2. Effect of APE/Ref-1 and PAX8 on transcriptional activity of NIS and TPO promoters. Transfections were performed in HeLa cells as described in Materials and Methods. Transcriptional activity was normalized for transfection efficiency by using the RSV-CAT construct. Each bar represents the mean value ± SD of three independent transfection experiments.

 
APE/Ref-1 activates the DNA-binding of the ubiquitous transcription factor Egr-1 (24). Thus, to explain the APE/Ref-1 effect in the absence of PAX8, a cotransfection experiment was performed in which the combined effects of Egr-1 and APE/Ref-1 on NIS promoter were tested. As shown in Fig. 3Go, in HeLa cells, cotransfection of the Egr-1 expression vector up-regulated NIS promoter, and this effect was potentiated by the concomitant transfection of the APE/Ref-1 expression vector. These data indicate that the PAX8-independent effect of APE/Ref-1 on NIS promoter was, at least in part, exerted by up-regulation of the Egr-1 transcriptional activity. Accordingly, several canonical Egr-1 binding sites are present in the human NIS promoter (data not shown).



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  		FIG. 3. Effect of APE/Ref-1 and Egr-1 on transcriptional activity of NIS promoter. HeLa cells were transfected as described in Materials and Methods. Transcriptional activity was normalized for transfection efficiency by using the RSV-CAT construct. Each bar represents the mean value ± SD of three independent transfection experiments. P values were calculated by the Student’s t test.

 
In the next set of experiments, we tested whether the APE/Ref-1 effect on NIS promoter was functioning also in thyroid tumor cells. Experiments were first performed in TPC-1 cell line derived from human thyroid papillary tumors, which show low levels of NIS transcript (25). As expected, the basal activity of NIS promoter was markedly reduced in these cells compared with the normal thyroid cell line FRTL-5. In fact, as shown in Table 1Go, by using either the CMV or the RSV promoter as reference promoter, the activity of the NIS promoter was lower in TPC-1 with respect to FRTL-5 cells. These data confirm previous observations obtained with other thyroid papillary cancer cell lines (26). Cotransfection of TPC-1 cells with the PAX8 expression vector alone determined only a 2-fold increase of NIS promoter activity (Fig. 4Go); interestingly, no enhancement of PAX8 effect was detectable in the presence of Ref-1, which, in addition, did not exert any important effect when expressed by itself (Fig. 4Go). Similar data were obtained when a different human cell line derived from human thyroid papillary tumor, B-CPAP (27), was analyzed (data not shown). These findings suggest that one of the reasons why NIS gene transcription is reduced in tumor cells is the lack of the activating effect exerted by APE/Ref-1. A possible explanation of such a behavior of thyroid tumor cells is the absence of a correct translocation of APE/Ref-1 in the nuclear compartment of these cells, as previously reported (22), which may represent a major limit for the PAX8 effects.


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  		TABLE 1. Activity of NIS promoter in FRTL-5 and TPC-1 cell lines

 


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  		FIG. 4. Effect of APE/Ref-1 and PAX8 on transcriptional activity of NIS promoter in TPC-1 cells. TPC-1 cells were transfected as described in Materials and Methods. Transcriptional activity was normalized for transfection efficiency by using the RSV-CAT construct. Each bar represents the mean value ± SD of three independent transfection experiments.

 
At present, the attempts to restore NIS expression in transformed thyroid cells have been based on activation of nonspecific pathways by means of using histone deacetylase inhibitors or demethylating agents (28, 29, 30), but such approaches were not always effective in all transformed thyroid cell lines (26). Retinoic acid also has been tested for a redifferentiation strategy, successfully in vitro (31) but not in vivo (32). An alternative way may be represented by acting on more thyroid-specific pathways of transcriptional activation of the NIS gene. Our present data, however, demonstrate that the recovery of thyroid-specific transcription factor expression is not sufficient for appearance of the correct function of the NIS gene promoter, suggesting that far more complex regulatory mechanisms, involving cofactors and their functional interaction with specific enhancer or silencers, are involved in the reduced/lost expression of the NIS gene in thyroid tumor cells. In particular, our data suggest a role for the loss of APE/Ref-1 nuclear expression, as a limit of PAX8 effects on the NIS promoter activity. It is of interest to note that two redox potential-sensitive factors (APE/Ref-1 and Egr-1) up-regulate NIS promoter activity. The redox potential is very important for the hormonogenetic activity of the thyroid follicular cell (33). Thus, it may be suggested that redox potential controls levels of NIS expression in vivo. Future work is required to address this issue.


   Acknowledgments
 
We are grateful to Dr. U. Loos for providing us with the clone containing 2.4 kb of 5' genomic sequence for the NIS promoter.


   Footnotes
 
This work was supported by the Italian Ministry of Health (to S.F.) and by grants from Ministero dell’Istruzione dell’Universita e della Ricerca Scientifica e Tecnologica (Cofin 2001) (to S.F., R.S., D.R., and G.D.).

Abbreviations: APE/Ref-1, Apurinic apyrimidinic endonuclease/redox factor 1; CAT, chloramphenicol-acetyl-transferase; CMV, cytomegalovirus; Egr-1, early growth response-1; LUC, luciferase; NIS, sodium/iodide symporter; RSV, Rous sarcoma virus; TPO, thyroperoxidase.

Received September 18, 2003.

Accepted for publication November 10, 2003.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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