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Na⁺/I^- Symporter Distribution in Human Thyroid Tissues: An Immunohistochemical Study¹

Departments of Pathology (B.C., M.T.), Nuclear Medicine (E.B., M.S.), and Clinical Biology (F.T., J.-M.B.), Institut Gustave-Roussy, 94805 Villejuif, France; and Dipartimento di Medicina Sperimentale e Clinica, Policlinico Mater Domini (S.F.), 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Dr. B. Caillou, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.

	Abstract

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Antipeptide antibodies raised against the carboxyl-terminal region of the human sodium/iodide (Na⁺/I^-) symporter (hNIS) were used to investigate by immunohistochemistry the presence and distribution of the hNIS protein in normal thyroid tissues, in some pathological nonneoplastic thyroid tissues, and in different histotypes of thyroid neoplasms. In normal thyroid tissue, staining of hNIS protein was heterogeneous and limited to a minority of follicular cells that were in close contact with capillary vessels. In positive cells, immunostaining was limited to the basolateral membrane. In contrast, in Graves’ disease the majority of follicular cells expressed the hNIS protein. In autoimmune thyroiditis, the number of hNIS-positive cells, was similar to that found in normal tissue. These positive cells were found essentially close to lymphocytic infiltrates. This observation supports the concept of hNIS as an autoantigen. In diffuse nodular hyperplasia, hNIS staining was heterogeneous, but the number of hNIS-positive cells exceeded that found in normal tissue. In well differentiated follicular or papillary carcinoma, the number of hNIS-positive cells was significantly lower than in normal tissue. In poorly differentiated follicular carcinoma, the number of hNIS-positive cells was less than that found in well differentiated carcinoma, or there were no positive cells. Interestingly, in all of these thyroid tissues, the number of follicular cells exhibiting TSH receptor (TSHR) immunoreactivity was greater than the number of hNIS-positive cells. As hNIS expression appears to be related to TSHR stimulation, the decreased number of TSHR-positive cells in cancers may contribute to the reduced capacity of neoplastic cells to concentrate iodide. In one patient with a follicular cancer with an absence of hNIS immunostaining, the total body ¹³¹I scan showed no uptake in metastatic tissue. In three cancers with positive hNIS cells, the ¹³¹I scan showed uptake in lymph node metastases. This suggests that immunodetection of hNIS could predict radioiodine uptake in thyroid cancers.

	Introduction

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IODIDE concentration in the thyroid gland is 20- to 40-fold that in the blood. Iodide uptake occurs across the basolateral membrane of thyroid follicular cells via an active transport process mediated by the sodium/iodide (Na⁺/I^-) symporter (NIS), which belongs to the Na⁺/glucose cotransporter family (1, 2). Recent structural analyses of the members of the Na⁺/glucose cotransporter family suggest membrane proteins composed of 13 putative transmembrane domains (3, 4). The human NIS (hNIS) gene has recently been cloned, and it encodes a 643-amino acid residue-long protein that is 84% homologous to the rat NIS (5, 6).

TSH regulates every step of thyroid iodine metabolism through the cAMP cascade. Iodine uptake has been demonstrated to be under the control of TSH, as stimulation by TSH increases radioiodine uptake in vivo and in vitro as well as hNIS expression in cultured thyroid cells (7, 8). Variations in hNIS expression or in its functional activity may contribute, together with other factors (such as the iodine supply), to the differences in radioiodine uptake observed among thyroid diseases. Inactivating mutations in the hNIS gene have been described in patients with congenital hypothyroidism and low iodine uptake (9, 10, 11). Radioiodine uptake is increased in patients with Graves’ disease and decreased in benign and malignant thyroid tumors. Increased hNIS expression has been found in Graves’ thyroid tissue (7), whereas hNIS expression was lower in thyroid carcinoma than in normal thyroid tissue (6). However, an increased expression of hNIS was recently reported in the majority of papillary thyroid carcinomas studied (12). On the other hand, transfection of the hNIS gene into malignant rat thyroid cells that did not concentrate iodide resulted in a 60-fold increase in cells accumulating ¹²⁵I in vitro (13). These observations suggest that both the expression and functional integrity of hNIS are critical for iodide transport and accumulation. This is of paramount importance in patients with differentiated thyroid carcinoma in whom radioiodine is used to both detect and eradicate neoplastic tissue (14, 15).

In the present report we have examined hNIS expression in thyroid tissues using purified polyclonal antibodies raised against a synthetic peptide mimicking the carboxyl-terminal region of this protein. Site-directed antibodies have proven useful for the detection and analysis of the topology of various transmembrane proteins, and this approach has recently been used to characterize rat NIS (16, 17). Immunohistochemical studies were designed for the detection and localization of hNIS at the cellular level in tissue sections obtained from normal thyroid tissues and from patients with benign and malignant conditions. hNIS expression was also compared to that of the TSH receptor (TSHR).

	Materials and Methods

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Peptide synthesis

A peptide spanning the hNIS-(615–643) region was synthesized by a conventional solid phase method using an PE Applied Biosystems model 431A peptide synthesizer (Foster City, CA). After completion of synthesis, the identity and purity of the peptide were verified by 1) amino acid analysis on an Alpha LKB analyzer (Rockville, MD), 2) high performance liquid chromatography, and 3) microsequence analysis of each high performance liquid chromatography peak on an automated PE Applied Biosystems 477A protein sequencer. The hNIS-(615–643) peptide was conjugated to keyhole limpet hemocyanin using benzidine as the coupling agent.

Production and characterization of antipeptide antisera to hNIS

Two rabbits were immunized by intradermal injection of the hNIS-(615–643) synthetic peptide-carrier conjugate. After three subsequent boosts at 3-week intervals, animals were bled, and their sera were tested in an enzyme-linked immunosorbent assay. Antisera, at various dilutions, were checked for their capacity to react with the hNIS-(615–643) synthetic peptide coated on microtiter plates. Antibody binding was then revealed by peroxidase-labeled goat antirabbit antibody (Nordic, Tilburg, The Netherlands). The anti-NIS antiserum with the highest titer was purified by affinity chromatography on a protein A-Sepharose CL4b column run on a fast protein liquid chromatography device (Pharmacia LKB, Uppsala, Sweden). Competitive experiments were generated, as previously described (18). The monoclonal antibody directed against the human TSHR (R171) was provided by Prof. E. Milgrom (INSERM U-135, Bicetre, France) (19).

Immunohistochemistry

Normal thyroid samples were taken at a distance from solitary thyroid adenomas (n = 5). Pathological thyroid tissue specimens were obtained from patients suffering from Graves’ disease (n = 2), autoimmune thyroiditis (n = 2), diffuse nodular hyperplasia (n = 2), benign adenoma (n = 6), and follicular carcinoma (n = 5; comprising one well differentiated, minimally invasive; one well differentiated, widely invasive; and three poorly differentiated, widely invasive lesions), and papillary carcinoma (n = 9; of which four were follicular variants). These pathological specimens were classified according to WHO recommendations (20).

Specimens were frozen at -70 C in isopentane and stored in liquid nitrogen. Serial frozen cryostat tissue sections (5 mm) were cut and fixed in acetone for 10 min. These sections were then incubated with either the anti-NIS antiserum or the anti-TSHR monoclonal antibody, diluted at 1:500, for 30 min. Whole and purified anti-NIS antisera were diluted at 1:750 and 30 µg/mL, respectively. Sections were washed three times in Tris-HCl buffer for 5 min each time and then incubated in a biotinylated antibody (K674, Dako Corp., Carpinteria, CA). They were again washed three times and incubated with alkaline phosphatase-labeled streptavidin (K674, Dako Corp.) for 10 min. After three further washes, staining was completed after incubation with substrate chromogen solution (K699 fast red, Dako Corp.). Sections incubated with irrelevant antibodies (preimmune serum) or with the anti-hNIS antiserum preabsorbed with the corresponding excess peptide were used as negative controls.

Thyroid and ¹³¹I total body scans

Thyroid scintigraphy was performed in all patients with palpable thyroid nodules or goiter. In patients who had undergone thyroidectomy for thyroid carcinoma, a ¹³¹I total body scan was performed after the withdrawal of the thyroid hormone, with either 3.7 gigabecquerels (100 mCi) of radioiodine for ablation of thyroid remnants or 74–180 megabecquerels for follow-up total body scan. However, ¹³¹I uptake in neoplastic tissue could be assessed only in patients with residual disease outside the thyroid bed.

	Results

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Production and characterization of antipeptide antisera to hNIS

Rabbit antiserum titers obtained after immunization with the hNIS-(615–643) synthetic peptide-carrier conjugate were determined by enzyme-linked immunosorbent assay. Both animals produced antisera exhibiting high affinity binding to the synthetic carboxyl-terminal portion of the hNIS protein. Competitive inhibition experiments (data not shown) indicated that the affinity of these antisera for the synthetic peptide was approximately 2 x 10^-6 mol/L. The antiserum displaying the highest titer (10^-5) was purified by affinity chromatography; whole and purified antiserum provided similar immunohistochemical results.

Staining with hNIS in control tissues (muscle, thymus) was negative. Furthermore, applying the hNIS antiserum preincubated with the corresponding excess peptide led to negative immunohistochemical results (Fig. 1B).

View larger version (120K): [in this window] [in a new window]   Figure 1. Expression and localization of hNIS protein in human thyroid tissues. A, Heterogeneous distribution of hNIS protein (arrows) in normal thyroid tissue (magnification, x200). B, Control on the same tissue as A immunostained with anti-hNIS purified antiserum preabsorbed with the corresponding excess peptide (magnification, x200). C, Basolateral localization of hNIS protein in normal follicular cells. Note the more intense immunostaining in the basal part (large arrows) of the cells and the unstained apical part (small arrows; magnification, x1000). D, hNIS immunostaining in thyroid tissue corresponding to Graves’ disease. The great majority of follicular cells are strongly immunostained (magnification, x200). E, Autoimmune thyroiditis. hNIS immunostaining of follicular cells in contact with lymphocytes (arrows) around a neopostcapillary venule (*; magnification, x200) is shown. F, Nodular thyroid hyperplasia in which hNIS immunostaining is restricted to proliferating follicular cells (arrows; magnification, x160). G, Negative hNIS immunostaining in a papillary carcinoma (arrows on the left), whereas surrounding normal tissue (on the right) is strongly hNIS positive (magnification, x200). H, Papillary carcinoma. Only a small percentage of cancer cells are immunostained for hNIS protein. Note that positive cells are more frequently located in follicular structures (magnification, x200).

The results of the immunohistochemical studies are summarized in Table 1. The percentages of hNIS and TSHR immunostained follicular cells are indicated according to histopathological classification.

The follicular epithelial cells of all normal thyroid specimens exhibited a heterogeneous pattern when stained with hNIS antibodies. Inside a given follicle, isolated follicular cells were strongly immunostained by the anti-hNIS antiserum and were totally distinct from weakly positive or negative cells (Fig. 1A). A similar staining pattern was present in all follicles, but some follicles had a higher number of strongly hNIS-positive cells that were either grouped together or isolated. A different pattern was observed for the TSHR, which was consistently present in all normal follicular cells. In positive cells, hNIS staining was confined to the basolateral membrane (Fig. 1C). Basal staining was stronger than lateral staining. Stromal cells, lymphocytes, intrafollicular macrophages, and vascular endothelial cells did not react with the hNIS antibody.

Graves’ disease

The majority of the follicular cells were strongly immunostained by the antiserum (Fig. 1D).

Autoimmune thyroiditis

The follicular cells in contact with lymphocytes exhibited strong hNIS immunostaining, whereas those distant from lymphocytic infiltrates were generally negative or weakly immunostained (Fig. 1E).

Diffuse nodular hyperplasia

In macrofollicular hyperplasia, hNIS immunostaining displayed a characteristic pattern. In the large follicles, there was a distinct zone of strongly positive proliferating follicular cells, whereas nonproliferating cells were negative (Fig. 1F). Some macrofollicles displayed several areas of proliferating hNIS-positive cells. In normo- or microfollicular hyperplasia, hNIS immunostaining was similar to that in normal thyroid tissue, but the number of positive cells was generally greater. All follicular cells were immunostained for the TSHR.

Adenoma

In six adenomas that appeared to be hypofunctioning at thyroid scintigraphy, no hNIS immunostaining was detectable in the majority of follicles. Only a few follicles were stained, and in these positive follicles, the number of positive cells was smaller than that in normal thyroid tissue. In contrast, all follicular cells were immunostained for the TSHR (data not shown).

Follicular carcinoma

In the minimally invasive follicular carcinoma and in widely invasive or poorly differentiated follicular carcinomas, either a small minority of tumor cells were immunostained by the anti-hNIS antiserum or immunostaining was absent. The number of positive cells was apparently higher in well differentiated than in poorly differentiated cancers. In contrast, most tumor cells were positive for the TSHR (data not shown), but staining was heterogeneous and weaker than that in normal thyroid tissue.

Papillary carcinoma

In papillary carcinoma, hNIS immunostaining was negative or positive in only a few tumor cells (Fig. 1G). In the mixed papillary and follicular type, positivity was generally located in follicular structures (Fig. 1H). In these cases, the number of positive cells for TSHR was lower than that in normal tissue but much greater than that for hNIS (data not shown). In the follicular variant of papillary carcinoma, hNIS immunostaining was nonuniform. However, some tumor follicles showed positive cells, as in normal tissue. Immunostaining for TSHR was positive in most tumor cells (data not shown), but staining was heterogeneous and weaker than that in normal thyroid tissue.

Total body ¹³¹I scan

Assessment of ¹³¹I uptake in neoplastic tissue in vivo was possible in four patients with lymph node metastases from a thyroid carcinoma. In one patient, there was no detectable uptake and no hNIS immunostaining. The other three patients had uptake in lymph node metastases, and hNIS expression, albeit low, was found in the primary thyroid tumor (Table 2).

	Discussion

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In normal thyroid tissue, hNIS expression was limited to a minority of follicular cells. In line with its physiological role, hNIS was expressed in cells located close to capillary vessels. In contrast, all follicular cells were positive for the TSHR. This marked discrepancy between TSHR and hNIS immunostaining suggests that other factors, functioning in concert with TSH, modulate hNIS expression in normal thyroid cells. This is consistent with the heterogeneity of iodine distribution in thyroid cells, as shown by autoradiography and more recently by ion microscopy (21). In contrast, in overstimulated thyroid tissue, such as in Graves’ disease, the great majority of follicular cells display strong hNIS immunostaining. This observation is in agreement with previous in vitro studies on rat and human thyroid cells that clearly indicate that hNIS expression is TSH induced (8, 17), being increased in Graves’ thyroid tissue (7).

In diffuse nodular hyperplasia, hNIS expression was heterogeneous and often confined to proliferating cells located at one pole of the follicle. In contrast, all follicular cells were TSHR positive. This is in agreement with data on the pathogenesis of nodular goiter, in which functional activity varies widely between follicles and even between individual cells within the same follicle (22).

In autoimmune thyroiditis, strong hNIS staining was observed in cells in close contact with lymphocytes. hNIS has recently been considered as a major autoantigen in autoimmune thyroiditis along with thyroglobulin, thyroperoxidase, and TSHR (23, 24) and may attract cytotoxic lymphocytes. The heterogeneous hNIS distribution in these lesions can be related to tissue modifications due to lymphocytic infiltrate.

Adenomas that were hypofunctioning at thyroid scintigraphy showed weak heterogeneous hNIS staining compared to that of normal tissue or showed no staining. In minimally or widely invasive follicular carcinomas, results were similar to those observed in nonfunctioning adenomas. In papillary carcinomas, hNIS staining was heterogeneous but much weaker than that in normal tissue and was mostly found in follicular structures. TSHR staining was also heterogeneous and weaker in these tumors than in normal tissue. This could account in part for the low number of hNIS-positive cells. This weak hNIS protein expression in these cancers is consistent with their low iodide-trapping ability and the low messenger ribonucleic acid level, as shown by Northern blot analysis (6).

Recently, Saito et al. (12) found in the majority of papillary carcinomas an increase in hNIS expression at the messenger ribonucleic acid and protein levels. Moreover, cytoplasmic localization of hNIS immunostaining was demonstrated, whereas, as shown in Fig. 1C, we have found that hNIS positivity was restricted to the basolateral membrane of positive thyroid cells. This localization, similar to that observed for TSHR, corresponds exactly to the expected localization of a membrane transporter. These discordant results may be due to methodological differences, particularly to distinct peptide immunogens and/or to the procedure used for fixation of thyroid specimens.

Although the number of cases studied with radioiodine scans is low, it is noteworthy that three cases with iodine uptake in lymph nodes metastases had positive hNIS cells in the primary tumors, whereas no positive hNIS cells were found in the carcinoma with no iodine uptake in residual neoplastic tissue. These limited, but quite striking, findings suggest that hNIS-positive cells detected in primary thyroid tumors could be predictive of radioiodine uptake by neoplastic thyroid and metastatic tissues.

	Acknowledgments

 
We are indebted to Jean-Pierre Levillain and Mireille Le Maout for expert technical assistance in the production of peptides and antibodies. We also thank Lorna Saint-Ange for editing the manuscript.

	Footnotes

 
¹ This work was supported by grants from the Comité du Val de Marne de la Ligue Nationale Contre le Cancer, the Féderation Nationale des Groupements des Entreprises Françaises et Monégasques dans la Lutte Contre le Cancer (to J.M.B.), and the Associazione Italiana per la Ricerca sul Cancro (to S.F.).

Received February 12, 1998.

Revised June 12, 1998.

Accepted July 17, 1998.

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				K. Taki, T. Kogai, Y. Kanamoto, J. M. Hershman, and G. A. Brent A Thyroid-Specific Far-Upstream Enhancer in the Human Sodium/Iodide Symporter Gene Requires Pax-8 Binding and Cyclic Adenosine 3',5'-Monophosphate Response Element-Like Sequence Binding Proteins for Full Activity and Is Differentially Regulated in Normal and Thyroid Cancer Cells Mol. Endocrinol., October 1, 2002; 16(10): 2266 - 2282. [Abstract] [Full Text] [PDF]

				J.-K. Chung Sodium Iodide Symporter: Its Role in Nuclear Medicine J. Nucl. Med., September 1, 2002; 43(9): 1188 - 1200. [Abstract] [Full Text] [PDF]

				F. Arturi, L. Lacroix, I. Presta, D. Scarpelli, B. Caillou, M. Schlumberger, D. Russo, J.-M. Bidart, and S. Filetti Regulation by Human Chorionic Gonadotropin of Sodium/Iodide Symporter Gene Expression in the JAr Human Choriocarcinoma Cell Line Endocrinology, June 1, 2002; 143(6): 2216 - 2220. [Abstract] [Full Text] [PDF]

				J. W. A. Smit, J. P. Schroder-van der Elst, M. Karperien, I. Que, M. Stokkel, D. van der Heide, and J. A. Romijn Iodide Kinetics and Experimental 131I Therapy in a Xenotransplanted Human Sodium-Iodide Symporter-Transfected Human Follicular Thyroid Carcinoma Cell Line J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1247 - 1253. [Abstract] [Full Text] [PDF]

				M. Tonacchera, P. Viacava, P. Agretti, G. de Marco, A. Perri, C. di Cosmo, M. de Servi, P. Miccoli, F. Lippi, A. G. Naccarato, et al. Benign Nonfunctioning Thyroid Adenomas Are Characterized by a Defective Targeting to Cell Membrane or a Reduced Expression of the Sodium Iodide Symporter Protein J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 352 - 357. [Abstract] [Full Text] [PDF]

				W.-A. Nieuwlaat, A. R. Hermus, F. Sivro-Prndelj, F. H. Corstens, and D. A. Huysmans Pretreatment with Recombinant Human TSH Changes the Regional Distribution of Radioiodine on Thyroid Scintigrams of Nodular Goiters J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5330 - 5336. [Abstract] [Full Text] [PDF]

				M. R. Castro, E. R. Bergert, J. R. Goellner, I. D. Hay, and J. C. Morris Immunohistochemical Analysis of Sodium Iodide Symporter Expression in Metastatic Differentiated Thyroid Cancer: Correlation with Radioiodine Uptake J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5627 - 5632. [Abstract] [Full Text] [PDF]

				T. Kogai, J. M. Hershman, K. Motomura, T. Endo, T. Onaya, and G. A. Brent Differential Regulation of the Human Sodium/Iodide Symporter Gene Promoter in Papillary Thyroid Carcinoma Cell Lines and Normal Thyroid Cells Endocrinology, August 1, 2001; 142(8): 3369 - 3379. [Abstract] [Full Text] [PDF]

				C. Spitzweg, K. J. Harrington, L. A. Pinke, R. G. Vile, and J. C. Morris The Sodium Iodide Symporter and Its Potential Role in Cancer Therapy J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3327 - 3335. [Full Text] [PDF]

				B. Caillou, C. Dupuy, L. Lacroix, M. Nocera, M. Talbot, R. Ohayon, D. Deme, J.-M. Bidart, M. Schlumberger, and A. Virion. Expression of Reduced Nicotinamide Adenine Dinucleotide Phosphate Oxidase (ThoX, LNOX, Duox) Genes and Proteins in Human Thyroid Tissues J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3351 - 3358. [Abstract] [Full Text] [PDF]

				U. Haberkorn, M. Henze, A. Altmann, S. Jiang, I. Morr, M. Mahmut, P. Peschke, W. Kübler, J. Debus, and M. Eisenhut Transfer of the Human NaI Symporter Gene Enhances Iodide Uptake in Hepatoma Cells J. Nucl. Med., February 1, 2001; 42(2): 317 - 325. [Abstract] [Full Text]

				D. A. Huysmans, W.-A. Nieuwlaat, R. J. Erdtsieck, A. P. Schellekens, J. W. Bus, B. Bravenboer, and A. R. Hermus Administration of a Single Low Dose of Recombinant Human Thyrotropin Significantly Enhances Thyroid Radioiodide Uptake in Nontoxic Nodular Goiter J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3592 - 3596. [Abstract] [Full Text]

				A. Boland, M. Ricard, P. Opolon, J.-M. Bidart, P. Yeh, S. Filetti, M. Schlumberger, and M. Perricaudet Adenovirus-mediated Transfer of the Thyroid Sodium/Iodide Symporter Gene into Tumors for a Targeted Radiotherapy Cancer Res., July 1, 2000; 60(13): 3484 - 3492. [Abstract] [Full Text]

				A. De la Vieja, O. Dohan, O. Levy, and N. Carrasco Molecular Analysis of the Sodium/Iodide Symporter: Impact on Thyroid and Extrathyroid Pathophysiology Physiol Rev, July 1, 2000; 80(3): 1083 - 1105. [Abstract] [Full Text] [PDF]

				J.-M. Bidart, C. Mian, V. Lazar, D. Russo, S. Filetti, B. Caillou, and M. Schlumberger Expression of Pendrin and the Pendred Syndrome (PDS) Gene in Human Thyroid Tissues J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2028 - 2033. [Abstract] [Full Text]

				I. E. Royaux, K. Suzuki, A. Mori, R. Katoh, L. A. Everett, L. D. Kohn, and E. D. Green Pendrin, the Protein Encoded by the Pendred Syndrome Gene (PDS), Is an Apical Porter of Iodide in the Thyroid and Is Regulated by Thyroglobulin in FRTL-5 Cells Endocrinology, February 1, 2000; 141(2): 839 - 845. [Abstract] [Full Text] [PDF]

V. Lazar, J.-M. Bidart, B. Caillou, C. Mahé, L. Lacroix, S. Filetti, and M. Schlumberger Expression of the Na+/I- Symporter Gene in Human Thyroid Tumors: A Comparison Study with Other Thyroid-Specific Genes J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3228 - 3234. [Abstract] [Full Text]