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Expression of the Apical Iodide Transporter in Human Thyroid Tissues: A Comparison Study with Other Iodide Transporters

Departments of Clinical Biology (L.L., T.I., J.-M.B.), Statistics (N.B.), Pathology (M.T., B.C.), Nuclear Medicine (M.S.), Commissariat à l’Energie Atomique-LRC29V, and Centre National de la Recherche Scientifique (CNRS)-UMR1582 (C.M.), Institut Gustave-Roussy, 94805 Villejuif Cedex, France; and Commissariat à l’Energie Atomique-LRC16V (T.P.), Université Nice Sophia-Antipolis, CNRS-UMR6078, F-06238 Villefranche-sur-Mer, France

Address all correspondence and requests for reprints to: Jean-Michel Bidart. Department of Clinical Biology, Institut Gustave-Roussy, 94805 Villejuif Cedex, France. E-mail: bidart{at}igr.fr.

	Abstract

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Iodide transport by thyrocytes involves two transporters, namely the Na⁺/I ^- symporter located at the basolateral pole and possibly pendrin in the apical membranes of the cell. Recently, we identified a human gene and its protein product, designated hAIT, as a putative new transporter involved in iodide transfer across the apical membrane of thyrocytes. In the present report, we analyzed both hAIT gene and protein expressions in a large series of benign and malignant human thyroid tissues.

Using immunohistochemistry, hAIT staining was detected in normal thyroid tissue in about 10% of follicles; in positive follicles, 10–40% of thyrocytes, mostly the tall cells, were stained. In thyroid tissues obtained from patients with Graves’ disease and toxic adenomas, hAIT mRNA and protein levels were similar to those found in normal tissue. In hypofunctioning adenomas, hAIT mRNA levels were slightly decreased, and apical iodide transporter (AIT) immunostaining was similar to that observed in normal thyroid tissue. AIT staining was stronger in Hürthle cell adenomas and in microfollicular adenomas. In thyroid carcinomas, the mean and median hAIT mRNA levels were significantly decreased. Expression of AIT protein was undetectable in most papillary carcinomas and was weak but detectable in most follicular carcinomas; it was negative in anaplastic carcinomas.

	Introduction

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IN THYROID CELLS, iodide transport is mediated by several proteins (1). At the basolateral membrane, the sodium/iodide symporter or NIS (SLC5A5) catalyzes the active transport of iodide from blood into the cells (2, 3). At the apical membrane, pendrin, the product of the Pendred syndrome gene (PDS, SLC26A4), has been proposed to transfer iodide from the cell into the colloid, but many uncertainties still remain concerning its physiological role (4, 5, 6, 7).

Recently, we identified a new gene, located on 12q23, that shares a 70% similarity with NIS and is expressed in the thyroid gland (8). Functional in vitro experiments demonstrated that its gene product catalyzes iodide transfer but not iodide accumulation. Immunohistochemistry localized the protein at the apical pole of human thyroid cells. These observations suggest that the product of this new gene, designated hAIT (human apical iodide transporter), transfers iodide across the apical membrane of thyroid cells into the follicular lumen.

Abnormalities in the iodide transport mechanism have been depicted in pathological thyroid gland (9). Compared with normal thyroid tissue, NIS gene expression is higher in hyperfunctioning tissue from Graves’ disease or toxic adenoma and lower or even undetectable in hypofunctioning adenomas and carcinomas (10, 11, 12). In malignant tissues, recent observations suggest that impaired membrane targeting may explain in part the decreased iodide accumulation in thyroid cancer (13). Transcript levels of PDS and of its protein product, pendrin, were found within the normal range in hyperfunctioning tissues and in hypofunctioning adenomas and were profoundly decreased in thyroid carcinomas (14, 15).

In the present study, we analyzed hAIT gene expression using real-time kinetic quantitative PCR and protein expression using an immunohistochemical method based on antipeptide antibodies in a large series of normal, benign, and malignant human thyroid tissues, in which we recently studied several thyroid-related gene and protein expressions. The results of hAIT gene and protein expressions were then compared with those observed for NIS and PDS (10, 14).

	Materials and Methods

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Materials

Thyroid tissue samples were selected after histological examination and classified according to World Health Organization recommendations (16). Tissue samples selected for real-time quantitative PCR were as follows: hyperfunctioning tissues, including specimens from patients with Graves’ disease (n = 5) and toxic adenomas (n = 10); benign follicular adenomas that appeared hypofunctioning on thyroid scintigraphy (n = 24); papillary thyroid carcinomas (n = 42); and follicular thyroid carcinomas (n = 5). Paired samples of both normal and tumoral thyroid tissues were obtained from 14 patients with an unifocal papillary carcinoma. Normal thyroid samples, taken from the contralateral lobe at a distance from the tumor site, were used as calibrator materials in the real-time PCR analysis. For immunohistochemical studies, normal and pathological thyroid tissues were selected from the above series; tissue samples from two anaplastic carcinomas also were analyzed.

Except in patients with Graves’ disease or toxic adenoma, in whom serum TSH was undetectable, thyroid samples were obtained in euthyroid subjects, as assessed by serum TSH concentrations in the normal range at the time of surgery. All specimens were frozen at -70 C in isopentane and stored in liquid nitrogen in the tissue library of the Department of Pathology at Institut Gustave-Roussy. This study was performed in accordance with protocols previously approved by the local human studies committee.

Determination of mRNA level using real-time RT-PCR

To study hAIT gene expression in thyroid tissues, we developed a real-time quantitative RT-PCR method. To this aim, total RNA was isolated from tissue samples using the DNA/RNA extraction Midi kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. Quality of RNA was assessed by conventional gel electrophoresis and 1 µg total RNA for each sample was reverse-transcribed using random hexamers (Applied Biosystems, Foster City, CA) as previously described (10). The cDNAs were then diluted 1:20 in nuclease-free H₂O (Promega Corp., Madison, WI).

Oligonucleotide primers and TaqMan probe for hAIT gene were designed to be intron spanning and were purchased from Applied Biosystems (Table 1). Real-time quantitative PCR was achieved using cDNA equivalent of 20 ng total RNA/50 µl per tube using the TaqMan PCR core reagent kit according to the manufacturer’s instructions and was developed on the ABI Prism 7700 Sequence Detector (Applied Biosystems). To normalize for differences in the amount of total RNA added to the reaction, amplification of 18S ribosomal RNA was performed as an endogenous control (10). A sample of normal thyroid tissue was used as the calibrator (1x sample) for determining the relative expression of hAIT gene in tissues.

A 34-amino-acid peptide, spanning the COOH-terminal portion of hAIT, was synthesized by a conventional solid-phase method using a model 431A peptide synthesizer (Applied Biosystems). The identity and purity of the peptide were verified by 1) amino acid analysis on an Alpha LKB analyzer (LKB, Rockville, MD); 2) HPLC; and 3) microsequence analysis of each HPLC peak on an automated 477A protein sequencer (Applied Biosystems). This peptide was then conjugated to keyhole limpet hemocyanin using benzidine as the coupling agent, and two rabbits were immunized by intradermal injections of the synthetic peptide-carrier conjugate. After three subsequent boosts at 3-wk intervals, animals were bled, and their sera were tested in an ELISA, as previously described (14).

Western blot experiment

To confirm that the antibody interacts with hAIT, Western blot experiments were performed. Samples of extracellular cell membranes (15 µg) were prepared from SiHa cells either noninfected or infected by a recombinant hAIT adenovirus (our unpublished data). After dilution with NuPAGE lithium dodecyl sulfate sample buffer (4x) (Invitrogen, Cergy Pontoise, France) containing 10% dithiothreitol, proteins were separated by electrophoresis on SDS-10% NuPAGE Bis-Tris gels (Invitrogen). After blotting, the membrane was incubated with the hAIT polyclonal antibody at a dilution of 1:100. After washing, the membrane was incubated with a donkey antirabbit antibody conjugated with horseradish peroxidase (1:1000) (Amersham Biosciences, Orsay, France) and developed with an enhanced chemiluminescence detection kit (Amersham Biosciences).

Immunohistochemistry

Immunohistochemisty was performed on AFA (alcohol, formol, acetic acid)-fixed paraffin-embedded tissues. Tissue blocks were obtained from the archival material of the Pathology Department of Institut Gustave-Roussy. Briefly, 5-µm sections were initially deparaffinized by serial passages in xylene and in alcohol series. Endogenous peroxidase activity was quenched by incubation in 0.03% of hydrogen peroxide, in 0.1 M Tris-HCl buffer 1x (pH 7.6) for 5 min. Subsequently, microwave/pressure cooker pretreatment (three cycles of 5 min each) was performed in 1 mM EDTA buffer (pH 8).

Sections were subsequently incubated for 30 min at room temperature with the anti-hAIT antiserum diluted at 1:50. Sections were then washed three times in Tris-HCl 1x buffer for 5 min each time and incubated with a peroxidase-conjugated antibody for 15 min (peroxidase antirabbit/mouse Dako EnVision System cod.K 4003, Dako Corp., Carpinteria, CA). After three additional washes, peroxidase staining was revealed in diaminobenzidine tetrahydrochloride (Polysciences, Inc., Warrington, PA) with 0.1% of hydrogen peroxide, in Tris buffer 0.01 M (pH 7.2). Sections were counterstained with hematoxylin, dehydrated, and mounted. Negative controls were obtained by studying thyroid tissues incubated with preimmune antisera and immune sera preabsorbed with an excess of the corresponding peptide.

Statistical methods

The expression of hAIT gene detected in each histological group was compared with its expression in the 14 normal samples using the Wilcoxon’s test. The correlation between hAIT gene expression and those observed for NIS and PDS genes was studied on the whole series of thyroid samples using Spearman’s rank order correlation coefficient.

	Results

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Determination of mRNA levels

To validate the real-time PCR method, standard curves for hAIT and 18S ribosomal RNA were constructed from PCR products serially diluted in nuclease-free H₂O. Figure 1 shows the real-time PCR standard curve for the hAIT mRNA. The efficiency of the standard curve, as determined by its slope, allowed us to quantify the hAIT gene expression profile in each thyroid specimen by using the comparative threshold cycle (C_t) method according to the manufacturer’s instructions. The calibrator was used because the 1x sample and all other levels were expressed as an n-fold difference relative to the calibrator. The characteristics of the assay and the results for NIS and PDS gene expressions have been reported previously (10, 14).

View larger version (23K): [in this window] [in a new window]   FIG. 1. Calibration curve for hAIT mRNA using the TaqMan PCR analysis. Standard curve plotting the log of the input amount (nanograms of total starting RNA) vs. the Ct was determined as described in Materials and Methods. Ct represents the PCR cycle at which an increase in reporter fluorescence above a baseline signal was first detected.

Among the 14 specimens of normal thyroid tissues, mean and median hAIT gene expression levels were similar (Fig. 2 and Table 2). Mean and median NIS and PDS gene expression levels were also similar in these specimens.

View larger version (22K): [in this window] [in a new window]   FIG. 2. Box plots for hAIT gene expression levels according to the histological diagnosis. The box shows the limits of the middle half of the data; the bold line inside the box represents the median. Whiskers are drawn to the nearest value not exceeding a standard span (1.5x interquartile range) from the quartiles. Extreme points (outliers) are highlighted by a cross.

View larger version (54K): [in this window] [in a new window]   FIG. 3. Western blot experiment, characterization of hAIT polyclonal antibody. Samples of cell membranes were prepared from SiHa cells either noninfected (line Ni) or infected by a recombinant hAIT adenovirus (line hAIT). Polyclonal antibody against hAIT bound to a Mr 69-kDa protein corresponding to the expected Mr only in cell membrane extracts from infected SiHa cells.

View larger version (104K): [in this window] [in a new window]   FIG. 4. Expression and localization of hAIT and NIS proteins in human thyroid tissues. A, Apical localization of hAIT in normal tall thyrocytes. B, Cytoplasmic and basolateral localization of NIS in normal tall thyrocytes. C, Apical hAIT immunostaining in normal thyroid tissue. hAIT is present in a minority of thyrocytes inside a given follicle (arrows). D, Apical hAIT immunostaining in Graves’ disease. Note that the intensity of immunostaining is weaker than in normal tissue. E, Apical hAIT immunostaining in a microfollicular adenoma. Note that staining is stronger in smaller follicles. F, Apical AIT immunostaining in a case of Hürthle cell tumor. G, Papillary thyroid carcinoma. Most cells are negative. H, Papillary thyroid carcinoma. hAIT immunostaining at the apical membrane on isolated tumor cells (arrows). L, Lumen of the follicle. Magnification, x1000 in A, B, and D; x200 in C, E, F, and G; x400 in H.

In thyroid tissues obtained from patients with Graves’ disease and toxic adenomas, hAIT mRNA levels were in the normal range (Fig. 2 and Table 2). PDS mRNA levels were also in the normal range, but NIS mRNA levels were significantly increased. Immunohistochemistry showed that hAIT staining was similar or slightly reduced compared with that in normal thyroid tissue (Fig. 4D).

hAIT gene and protein expression in hypofunctioning thyroid adenomas

In hypofunctioning adenomas, the mean and median hAIT mRNA levels were slightly decreased in comparison with those observed in normal tissues (Fig. 2 and Table 2). In these specimens, PDS gene expression was only slightly decreased, whereas NIS mRNA levels were profoundly reduced. In the majority of samples, hAIT staining was similar to that observed in normal thyroid tissue and in the other samples was absent or weakly positive. Interestingly, hAIT staining was stronger in microfollicular adenomas and in Hürthle cell tumors (Fig. 4, E and F).

hAIT gene and protein expression in thyroid carcinomas

In thyroid carcinomas, the mean and median hAIT mRNA levels were significantly decreased (Fig. 2 and Table 2). PDS and NIS gene expression were also significantly decreased. Most papillary carcinomas were negative for hAIT staining (Fig. 4G) and, when positive, hAIT was detected at the apical pole of isolated cells (Fig. 4H). In a minority of tumor cells, diffuse staining was observed in the cytoplasm. Expression of hAIT protein was weak but detectable in most follicular carcinomas and was stronger in microfollicular carcinomas. Finally, AIT staining was negative in the two anaplastic carcinomas studied (data not shown).

Analysis of the correlation between the hAIT, hNIS, and PDS gene expressions

Using Spearman’s rank order correlation coefficient on the whole series of thyroid samples, hAIT gene expression better correlated with that of PDS gene (0.74) than with that of hNIS gene (0.61).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Iodide transport by thyrocytes is a two-step process involving transporters in the basolateral and in the apical membranes of the cell. Recently, we identified a new gene and its protein product, highly homologous to NIS, as a putative transporter that was involved in iodide transfer across the apical membrane of thyrocytes (8). Here, we report on both hAIT gene and protein expressions in a large series of benign and malignant human thyroid tissues.

In normal thyroid tissue, hAIT staining was confined to the apical membrane, the location previously reported, and that suggests that it may mediate passive iodide transfer to the follicular lumen (8). As observed for NIS and pendrin (12), a heterogeneous pattern of staining was found from one follicle to another, with about 10% of follicles being stained, and inside a positive follicle, fewer than half of the cells were stained. Positive staining was found mostly in supposedly active cells that are cells in small follicles and in tall columnar cells in normal and macrofollicles. The similar staining pattern for these three iodide transporters contrasts with the homogeneous expression observed for other thyroid-specific proteins, particularly the TSH receptor (17). This may reflect a functional modulation of the expression of the transporters, in line with the heterogeneity of iodide distribution in follicular cells (18).

hAIT gene and protein expressions were not significantly altered in hyperfunctioning tissues from Graves’ disease and toxic adenoma, suggesting that hAIT expression is less sensitive to the stimulatory effects of the TSH pathway. Also, hAIT gene and protein expression appeared to be normal or only slightly decreased in hypofunctioning adenomas. This pattern is similar to that observed for PDS/pendrin but different from that observed for NIS expression that is greatly increased in hyperthyroid tissues and decreased in hypofunctioning adenomas. These data point out the absence of relationship between hAIT and PDS/pendrin expressions and iodide uptake by the thyroid tissue that is indeed closely related to NIS expression. This also shows that NIS function is not significantly dependent upon AIT or PDS/pendrin expression. Finally, in thyroid carcinomas, hAIT, PDS/pendrin, and NIS expressions were profoundly decreased. These alterations may be related to the neoplastic process (19) and may also play a role in organification defects observed in neoplastic thyroid tissues.

	Footnotes

 
This work was supported by grants from the Commissariat à l’Energie Atomique (CEA-LRC16V) and Electricité De France.

Abbreviations: AIT, Apical iodide transporter; C_t, threshold cycle; hAIT, human AIT; M_r, relative molecular mass; NIS, sodium/iodide symporter; PDS, Pendred syndrome.

Received March 28, 2003.

Accepted November 13, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lacroix, L. Articles by Bidart, J.-M. Search for Related Content PubMed PubMed Citation Articles by Lacroix, L. Articles by Bidart, J.-M.