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Endocrinology Vol. 143, No. 6 2216-2220
Copyright © 2002 by The Endocrine Society

REPRODUCTION-DEVELOPMENT

Regulation by Human Chorionic Gonadotropin of Sodium/Iodide Symporter Gene Expression in the JAr Human Choriocarcinoma Cell Line

Franco Arturi, Ludovic Lacroix, Ivan Presta, Daniela Scarpelli, Bernard Caillou, Martin Schlumberger, Diego Russo, Jean-Michel Bidart and Sebastiano Filetti

Dipartimento di Medicina Sperimentale e Clinica (F.A., I.P., D.S., S.F.) and Scienze Farmacobiologiche (D.R.), Università di Catanzaro, Magna Graecia 88100 Catanzaro, Italy; Dipartimento di Scienze Cliniche (S.F.), Università La Sapienza, Rome, Italy; and Institut Gustave Roussy (L.L., B.C., M.S., J.-M.B.), 94805 Villejuif, France

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Dipartimento Scienze Cliniche, Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico 115, 00161 Rome, Italy. E-mail: . filetti{at}tin.it


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Sodium/iodide symporter (NIS) gene and protein expressions have been recently described in human cytotrophoblasts, emphasizing its potential function in the active transport of iodide from the mother to the fetus. In this study we analyzed NIS expression and function in the human JAr placental choriocarcinoma cell line.

Using real-time quantitative RT-PCR, we first demonstrated that NIS transcripts are expressed at a high level in JAr cells compared with other cell lines, including thyroid cancer cells. Functional analysis clearly showed that Jar cells are able to concentrate iodide in presence of hCG. Iodide accumulation increased after 2-h exposure to 5 IU/ml hCG, to 6-fold over the basal level after 8 h. This effect was reproduced using forskolin, the cAMP analog (Bu)2-cAMP, and phorbol acetate. Moreover, hCG increased both NIS mRNA after 2 h and NIS protein levels after 4 h, reaching a maximum after 8 h in both cases.

In conclusion, our data demonstrate that 1) NIS is expressed in JAr cells; 2) iodide transport in JAr cells is regulated by hCG and by cAMP-dependent and -independent mechanisms; 3) the stimulation of iodide uptake is due to an increase in both NIS mRNA and protein levels; and 4) JAr cells may represent an excellent in vitro model suitable to analyze the molecular mechanisms involved in iodide transport from mother to fetus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DURING PREGNANCY, fetal thyroid function depends largely on the functional activity of the placenta. The human fetal thyroid becomes able to accumulate iodide after 13 wk of gestation and then produces thyroid hormones that are needed for adequate development (1, 2). The iodide necessary for the fetal thyroid function comes in part from deiodination of iodothyronines within the placenta and in part from the passage of iodide from the maternal circulation to the fetal placental unit (3). An adequate iodide supply from mother to fetus is critical for normal growth and development of the fetus (4). Indeed, children of women who have low serum T4 levels during pregnancy due to profound iodide deficiency have a higher incidence of behavioral and neurological disorders (4). Although different studies demonstrated ion efflux and influx through the placenta (5), the molecular mechanism underlying iodide transplacental transport remains unknown in part. Moreover, an interesting and unresolved question is whether the passage of iodide from mother to fetus represents a passive transfer or involves an active mechanism.

The gene encoding the sodium/iodide symporter (NIS), the protein responsible for iodide transport at the basal membrane of the thyrocyte, has been recently cloned and characterized (6, 7). This has permitted an improvement of knowledge of the molecular mechanism underlying the loss or reduction of iodide trapping in thyroid cancer cells, both primary and metastatic (7, 8, 9, 10, 11, 12, 13). However, several studies have demonstrated that NIS expression is not strictly limited to the thyroid cells, but also occurs in different extrathyroidal tissues that are known to accumulate iodide (14). Particularly, we demonstrated that NIS is expressed in the cytotrophoblastic layer of the placenta and that its expression decreases during differentiation into syncytiotrophoblast (15).

In this study we showed that NIS mRNA is expressed in the JAr choriocarcinoma cell line, originating from a human malignant cytotrophoblastic tumor. The potential functional role of NIS in placenta was investigated by studying in vitro iodide uptake in these cells both under basal conditions and in the presence of hCG. The effects of hCG on the expression of NIS were then investigated at mRNA and protein levels.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell cultures
The JAr human choriocarcinoma cell line was grown in 12-well tissue culture dishes (for measurement of 125I uptake), in 35-mm diameter dishes (for measurement of iodide efflux), and in 100-mm diameter dishes (for RNA and protein extractions) in RPMI 1640 medium supplemented with 10% FBS and containing penicillin/streptomycin and amphotericin. All other cell lines used in this study were grown as instructed by American Type Culture Collection (Manassas, VA).

hCG
A highly purified preparation of hCG was obtained from Dr. Steven Birken (Columbia University, New York, NY) (16).

125I uptake
Uptake of 125I by JAr cells was measured as previously described (17). Briefly, cells were split and seeded into 12-well plates. After aspirating the culture medium, cells were washed with 1 ml HBSS (Life Technologies, Inc., San Giuliano Milanese, Italy) supplemented with 10 mM HEPES, pH 7.3.

125I uptake was initiated by adding to each well 500 µl buffered HBSS containing 0.1 µCi carrier-free Na125I and 10 µM NaI to obtain a specific activity of 20 mCi/mmol.

In half of the wells this assay buffer was supplemented with the NIS inhibitor KClO4 (10 µM) to control for specific uptake. After 40 min at 37 C in a humid atmosphere, the radioactive medium was aspirated, and cells were washed with 1 ml ice-cold HBSS. To determine the amount of 125I associated with the cells, 1 ml 95% ethanol was added to each well for 20 min and then transferred into vials for counting with a {gamma}-counter. Iodide uptake was expressed as picomoles per microgram DNA. Each experiment was performed at least twice in quadruplicate, and the FRTL-5 cells and CHO cells were used, respectively, as positive and negative controls.

Iodide efflux
For efflux studies, JAr cells were grown to 95% confluence in 35-mm diameter plates. The cells were washed and incubated in a shaking water bath for 60 min at 37 C with buffered HBSS containing 10 µM NaI and 1 µCi 125I. For efflux measurements, the medium was removed gently so as not to dislodge cells and was replaced with 1 ml nonradioactive medium every 2 min. The medium were buffered with 10 µM NaI. Incubation and all media were kept at 37 C. After removal of the last medium (20 min), cells were extracted with 1 ml ethanol for counting along with the previously collected medium samples. The total radioactivity present at the initiation of the efflux study was calculated by adding the counts in the final tissue extract and the summation of the medium counts.

Determination of mRNA level using real-time RT-PCR
Total RNA was extracted from the cells using the RNA fast kit (Genenco, M-Medical, Florence, Italy), following the manufacturer’s instructions. One microgram of total RNA was reverse transcribed in a 20-µl volume reaction using 50 U Moloney murine leukemia virus reverse transcriptase, 20 U ribonuclease inhibitor (PE Applied Biosystems, Foster City, CA), 1 mmol/liter dA/T/C/G (Amersham Pharmacia Biotech, Uppsala, Sweden), 5 mmol/liter MgCl2, 10 mmol/liter Tris-HCl (pH 8.3), 10 mmol/liter KCl, and 50 pmol/liter random hexamers (PE Applied Biosystems). The cDNAs were then diluted 1:20 in nuclease-free H2O (Promega Corp., Madison, WI). Real-time quantitative RT-PCR was conducted as previously described (11). Briefly, RT-PCR was achieved in 96 sample tubes/assay, using a cDNA equivalent of 20 ng/total RNA/50 µl·tube with the TaqMan PCR core reagent kit and 100 µM TaqMan probe and 200 µM of each primer for the NIS gene (15) according to the manufacturer’s instructions. PCR was developed on the ABI PRISM 7700 sequence detector (PE Applied Biosystems).

Protein extraction and Western blot analysis
Total proteins were extracted from JAr cells as follows. Confluent cells from three petri dishes were collected and homogenized in 1 ml buffer containing 250 mM sucrose, 10 mM HEPES-KOH (pH 7.5), 1 mM EDTA, 1 mM phenylmethylsulfonylfluoride, 10 µg/ml leupeptin, and 10 µg/ml aprotinin. The homogenate was centrifuged at 14,000 x g (4 C for 15 min), and the supernatant (which contained the whole cell lysate) was quantified spectrophotometrically using the Bradford method (18).

Thirty micrograms of protein were loaded on a 8% polyacrylamide gel and subjected to electrophoresis at a constant voltage (110 V). Electroblotting to a Hybond-P ECL nitrocellulose membrane (Amersham Pharmacia Biotech) was performed overnight at 15 V using a mini-Transblot electroblotting system. Blocking was performed using Dulbecco’s PBS/milk (PBS and 5% nonfat dry milk) for 1 h at room temperature. The membrane was then incubated with a 1:1000 dilution of affinity-purified rabbit anti-NIS polyclonal antibody or a 1:3000 dilution of mouse monoclonal antihuman ß-actin antibody for 1 h and 30 min in PBS/milk (19). After three 5-min washes in PBS, the membrane was incubated with a 1:2000 dilution of horseradish peroxidase-conjugated antirabbit or antimouse antibody in PBS/milk. After three 5-min washes in PBS, the protein was visualized by an ECL Western blot detection system (Amersham Pharmacia Biotech). Quantification was achieved by densitometric scanning.

Statistical analysis
Results are expressed as the mean ± SEM. Differences between different points of stimulation were analyzed by one-factor ANOVA, followed by t test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In vitro expressions of NIS in JAr cells
Human NIS gene transcript was analyzed in various human tumoral cell lines. A quantitative assessment of this mRNA transcript was provided by comparative amplification curves obtained using real-time RT-PCR (Table 1Go). A pool of five normal thyroid tissues was used as a calibrator for determining the relative expression of NIS gene in cell lines. Interestingly, JAr cells appeared to express higher amounts of NIS transcripts than the other cell lines, particularly the papillary thyroid carcinoma cell line BC-PAP (JAr vs. BC-PAP cells, P < 0.05).


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  		Table 1. NIS gene expression in human tumoral cell lines

 
Effects of hCG on 125I uptake by JAr cells
The ability of JAr cells to accumulate 125I depends on the presence of hCG in the culture medium. Indeed, low levels of 125I uptake could be detected in JAr cells grown without hCG. In JAr cells precultured in the presence of hCG (5 IU/ml), 125I uptake increased significantly and reached a maximum after 8 h (6-fold over basal levels; P < 0.001; Fig. 1Go). Both the initial and steady state uptakes of 125I were inhibited by the anion ClO4- in a dose-dependent manner (data not shown) and by ouabain, an inhibitor of the Na+,K+-adenosine triphosphatase (data not shown).



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  		Figure 1. Effect of hCG on iodide uptake in JAr cells stimulated with hCG. Iodide uptake was measured as described in Materials and Methods at the indicated hours after the addition of 5 IU/ml hCG at time zero. Iodide uptake is expressed as the mean ± SEM of values obtained from three different experiments (n = 3). a, P < 0.001, 2 h of stimulation with hCG vs. basal value; b, P < 0.001, 4 h of stimulation with hCG vs. basal value; c, P < 0.001, 8 h of stimulation with hCG vs. basal value; d, P = 0.002, 24 h of stimulation with hCG vs. basal value; e, P < 0.001, 48 h of stimulation with hCG vs. basal value (by ANOVA, followed by t test).

 
125I efflux was very rapid in JAr cells, up to 80% of the cellular radioactivity being released into the medium during the first 2 min (Fig. 2Go).



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  		Figure 2. Iodide efflux studies in JAr cells stimulated with hCG. JAr cells grown to 95% confluence in 35-mm diameter plates were incubated in a shaking water bath for 60 min at 37 C in HBSS buffer containing 10 µM NaI and 1 µCi 125I. To evaluate the iodide efflux, the medium was removed and replaced with 1 ml nonradioactive medium every 2 min. After removal of the last medium (20 min), cells were extracted using 1 ml ethanol (see Materials and Methods). The values shown are the counts per min remaining (as a percentage of the total) at the indicated times. The experiment was performed twice and no differences were found.

 
To determine whether hCG exerts its action through newly synthesized protein, JAr cells were grown in medium with or without 10 µg/ml cycloheximide, an inhibitor of protein synthesis. Cycloheximide markedly reduced the hCG-induced stimulation of iodide uptake (P < 0.001; Table 2Go).


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  		Table 2. Effects of cycloheximide (CH), forskolin (FSK), (Bu)2cAMP (DBC), and tetradecanoyl phorbol acetate (TPA) on iodide uptake in JAr cells stimulated with hCG

 
Then, we evaluated whether the stimulatory effect of hCG on iodide uptake was mimicked by cAMP. JAr cells were grown in medium containing 10 µM forskolin or 1 mM (Bu)2cAMP, and iodide uptake increased by 4- and 4.2-fold over basal levels, respectively (P < 0.001 and P = 0.001 respectively; Table 2Go). Similarly, we evaluated the effects of 12-O-tetradecanoyl phorbol 13-acetate (TPA; 200 mM), an activator of PKC, that increased iodide uptake 5-fold over basal levels (P < 0.001; Table 2Go).

Effects of hCG on NIS mRNA and protein levels in JAr cells
As shown in Fig. 3Go, NIS mRNA levels increased after 2 h of stimulation by hCG, reaching a maximum after 8 h (P < 0.01). Western blot analysis revealed that the NIS protein was expressed in JAr cells precultured in the absence of hCG (Fig. 4Go). After stimulation by hCG, NIS protein levels increased after 4 h, reaching a maximum after 8 h.



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  		Figure 3. Effects of hCG on NIS mRNA levels in JAr cells. The JAr human choriocarcinoma cell line was grown in 100-mm diameter dishes in medium without hCG (see Materials and Methods) and then exposed to 5 IU/ml hCG for the indicated periods of time. Total RNA was extracted from duplicate dishes of cells (as described in Materials and Methods), and RNA levels were determined using the real-time PCR method. To normalize the different amounts of total RNA added to the reaction, amplification of 18S ribosomal RNA was performed as the endogenous control. The data are expressed as the mean ± SEM of values obtained from at least three different experiments. a, P = 0.2, 2 h of stimulation with hCG vs. basal value; b, P < 0.05, 4 h of stimulation with hCG vs. basal value; c, P < 0.01, 8 h of stimulation with hCG vs. basal value; d, P = 0.01, 24 h of stimulation with hCG vs. basal value; e, P = 0.1, 48 h of stimulation with hCG vs. basal value (by ANOVA followed by t test).

 


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  		Figure 4. Effect of hCG on NIS protein expression in JAr cells. Western blot analysis was performed as described in Materials and Methods. A, Autoradiograph of a representative experiment. Control (0 h) was in the absence of hCG. B, The staining intensity is expressed as mean of values obtained from two different experiments. Basal values were normalized to 100%. The data are expressed as the mean ± SEM of values obtained from at least two different experiments. a, P = 0.03, 4 h of stimulation with hCG vs. basal value; b, P = 0.001, 8 h of stimulation with hCG vs. basal value; c, P = 0.4, 24 h of stimulation with hCG vs. basal value; d, P = 0.4, 48 h of stimulation with hCG vs. basal value (by ANOVA followed by t test).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The placenta transfers iodide and small amounts of thyroid hormones from mother to fetus (1). The molecular mechanisms of iodide transport from mother to fetus are not clear. Recently, we and others demonstrated NIS expression in normal human placenta (15, 20). We also showed that NIS is located preferentially in cytotrophoblast cells. Finally, using an in vitro model of isolated cytotrophoblast cells, NIS gene expression was found to decrease during the differentiation of cytotrophoblast cells that fuse to form the endocrine syncytiotrophoblast layer of the placenta (15). The aim of the present study was to investigate the expression of NIS in malignant cells derived from a human placental cytotrophoblast tumor and the potential role of hCG, a major hormone produced by the placenta, on NIS expression.

The JAr choriocarcinoma cell line expresses high levels of NIS mRNA compared with other malignant cell lines originating from various human tumoral tissues. NIS expression correlated with that observed in normal and tumoral tissues (21, 22). Particularly BC-PAP, a papillary thyroid carcinoma cell line, displays very low amounts of NIS transcripts, in agreement with decreased or absent NIS expression in thyroid tumoral tissues (8, 11). The MCF-7 breast cancer cell line also expresses NIS mRNA, in agreement with the expression of NIS reported in normal and tumoral mammary gland (23).

Normal as well as malignant placentas are known to secrete large amounts of hCG. Several observations also demonstrated that hCG/human LH receptor (CG/LHR) transcripts and immunoreactive receptor protein are expressed in invasive normal trophoblast as well as in choriocarcinoma cells, suggesting a possible role for the hormone in trophoblast invasion (24, 25). However, whereas endogenous production of hCG by the trophoblast in vivo implies an autocrine control of some physiological processes by hCG, malignant placental cells, as demonstrated using JAr cells, lack the ability to self-regulate hCG biosynthesis (26). The structure of testicular and placental CG/LHR appears to be different from that found in the ovary (27), and human choriocarcinoma cells display a higher basal rate of transcription of the CG/LHR gene compared with normal term pregnancy placenta (28). Finally, several reports indicate that the autocrine action of hCG may also be involved in hormone production and anion transport (29, 30). In this context we investigated whether iodide could be efficiently concentrated by JAr cells and the potential role of hCG on this transport.

Functional analysis clearly demonstrated that JAr cells are able to concentrate iodide in the presence of hCG. Furthermore, the mechanism of iodide uptake was specific, being perchlorate sensitive; it was markedly decreased by cycloheximide and mimicked by forskolin, the cAMP analog (Bu)2cAMP, and TPA. We also showed that hCG significantly increased NIS expression at both mRNA and protein levels. Indeed, after hCG stimulation NIS mRNA levels increased after 2 h, reaching a maximum after 8 h, and NIS protein levels increased after 4 h, reaching a maximum after 8 h.

These data demonstrate for the first time that hCG is able to stimulate iodide uptake in placental cells. In the past, several studies demonstrated that hCG was able to stimulate iodide uptake in thyroid cells (31, 32). At variance with thyroid cells, however, in JAr cells TPA in addition to cAMP pathway activators behave as functional stimulators. In contrast, activation of the PKC pathway has proven to have an inhibitory effect on iodide transport in thyrocytes (33, 34). This discrepancy may be attributed to functional characteristics of cytotrophoblasts (15) or to a peculiar feature of choriocarcinoma cells. Indeed, a previous observation using the JEG choriocarcinoma cell line indicated that both cAMP and phorbol ester response signal pathways converge at the level of transcriptional activation (35).

In conclusion, our data demonstrate that human NIS is expressed in the JAr choriocarcinoma cell line. The iodide transport in these cells appears to be regulated by hCG, which exerts its effects on iodide uptake through the stimulation of both NIS mRNA and protein expression. Together these data suggest that, like TSH in thyroid cells, hCG in placenta may play a critical role in iodide uptake, and JAr cells may represent an in vitro model suitable to analyze the molecular mechanisms involved in iodide transport from mother to fetus.


   Acknowledgments
 
We are grateful to Dr. C. Cloro for the statistical analysis.


   Footnotes
 
This work was supported by a MURST grant and a grant from the Associazione Italiana per la Ricerca sul Cancro (to S.F.) and by Electricité de France (to M.S.).

Abbreviations: LHR, LH receptor; NIS, sodium/iodide symporter; TPA, 12-O-tetradecanoyl phorbol 13-acetate.

Received November 14, 2001.

Accepted for publication February 12, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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F. Arturi, E. Ferretti, I. Presta, T. Mattei, A. Scipioni, D. Scarpelli, R. Bruno, L. Lacroix, E. Tosi, A. Gulino, et al.
Regulation of Iodide Uptake and Sodium/Iodide Symporter Expression in the MCF-7 Human Breast Cancer Cell Line
J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2321 - 2326.
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K. A. B. Knostman, J.-Y. Cho, K.-Y. Ryu, X. Lin, J. A. McCubrey, T. Hla, C. H. Liu, E. Di Carlo, R. Keri, M. Zhang, et al.
Signaling through 3',5'-Cyclic Adenosine Monophosphate and Phosphoinositide-3 Kinase Induces Sodium/Iodide Symporter Expression in Breast Cancer
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5196 - 5203.
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