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Iodide Symporter Gene Expression in Human Thyroid Tumors¹

Cattedra di Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica (F.A., E.C., S.F.), and Cattedra di Farmacologia, Facoltà di Farmacia (D.R.), Università di Catanzaro, 88100 Catanzaro; and Oncologia Sperimentale, Istituto Nazionale Tumori (P.V.), Milan, Italy; and Institut de Recherches Scientifiques sur le Cancer, Centre National de Recherches Scientifiques (J.-A.D., R.W., H.G.S.), 94802 Villejuif; and Institut Gustave Roussy (M.S., B.C.), 94805 Villejuif, France

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Cattedra di Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, Via T. Campanella, 88100 Catanzaro, Italy. E-mail: filetti{at}tin.it

	Abstract

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Expression of the Na⁺/I^- symporter (NIS) gene was investigated by RT-PCR in a selected series of 26 primary thyroid carcinomas (19 papillary, 5 follicular, and 2 anaplastic). Fifteen follicular adenomas (11 "cold " and 4 "hot" adenomas) were also studied. Five of 19 papillary thyroid cancer did not express NIS messenger ribonucleic acid (mRNA). In all but 1 follicular cancer, NIS transcript was fully detected. In anaplastic tissue, NIS mRNA was only barely detected in 1 case. All of the follicular thyroid adenomas except 1 expressed the NIS gene. In contrast, all tumors studied excluding the anaplastic histotype fully expressed thyroglobulin and thyroid peroxidase mRNA transcripts. In 2 patients, a lower expression (3- to 5-fold) of NIS mRNA was found in metastasis by dot blot analysis compared with those in both normal and primary neoplastic thyroid tissue. Four of 8 differentiated thyroid cancer patients selected for the presence of metastases with negative posttherapy ¹³¹I total body scan showed the lack of NIS gene expression in their primary cancer. This defect, at least in these cases, is a somatic and intrinsic lesion of the primary cancer cells and is not due to a dedifferentiation process in the metastatic tissue. The early detection of the loss of NIS gene expression in the primary cancer, therefore, may provide useful information for the management of differentiated thyroid cancer patients.

	Introduction

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THYROID carcinomas usually appear as nonfunctional ("cold" nodule) on thyroid scintiscan due to a decreased ability to concentrate radioiodine. This decrease is variable from one tumor to another, and no uptake can be detected either in vivo or in vitro in one fourth to one third of cases. Only rarely do they appear as hyperfunctioning ("hot" nodule) (1). Several reports have demonstrated a decreased ability to accumulate iodide and a variety of iodine metabolism abnormalities in thyroid cancer tissue (2). The recent cloning of the Na⁺/I^- symporter (NIS) (3, 4) has provided the possibility to better elucidate the mechanism by which thyroid iodide trapping is reduced in cancer cells.

Radioiodine represents a major diagnostic and therapeutic tool for the management of differentiated thyroid cancer (DTC) patients to ablate residual, recurrent, or metastatic tumors (5), and the presence and functional integrity of the NIS are prerequisites for iodine concentration by malignant cells. In the present study we examined the expression of the NIS gene in a series of different histotypes of thyroid carcinomas, both primary tumors and metastases.

	Subjects and Methods

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Patients

Forty-one thyroid tumors, collected at the Institut Gustave Roussy (Villejuif, France) and at the Thyroid Center (University of Catania, Italy), were examined. Tissues obtained at surgery were immediately frozen and stored in liquid nitrogen until analysis. Tumors were histologically classified according to WHO recommendations (6). The clinical and pathological features of the patients studied are shown in Table 1. Follow-up of thyroid cancer patients included thyroglobulin (Tg) measurements and total body ¹³¹I scan (TBS) using either 7.4–18.5 megabecquerels (2–5 mCi) or a high dose of radioiodine (3.7 gigabecquerels; 100 mCi), as previously reported (7). We also included some primary cancer tissues from patients who had metastases (with or without 3.7 gigabecquerels ¹³¹I uptake at TBS) during the follow-up.

Total RNA was extracted from fresh-frozen tissues using the RNA B^tm technique (Bioprobe Systems, Richmond, CA) following the manufacturer’s instructions, as previously described (8). The tumor tissues used for RNA isolation in this study were microdissected by a pathologist to exclude contamination of surrounding normal thyroid cells.

Complementary DNA (cDNA) was synthesized from 1 µg total RNA according to the protocol of the manufacturer (Boehringer Mannheim, Milan, Italy). The mixture was incubated at 25 C for 10 min and at 42 C for 60 min, heated to 99 C for 5 min, and then stored at -20 C. PCR amplification was performed using 5 µL cDNA, as previously described (9). Briefly, samples were subjected to 41 cycles of amplification, and PCR conditions were as follows: for the NIS and thyroid peroxidase (TPO) genes, denaturation at 94 C (1 min), annealing at 62 C (1 min), and extension at 72 C (1 min) for 40 cycles; for the Tg gene, denaturation at 94 C (1 min), annealing at 57 C (1 min), and extension at 72 C (1 min) for 40 cycles; the last cycle was 72 C for 7 min (1 cycle). Ten of 50 µL of the amplification products were then run on 1.5% Tris-borate-ethylenediamine tetraacetate agarose gel containing ethidium bromide and analyzed to confirm a positive or a negative outcome.

Primer oligonucleotides for the NIS gene were: 5' primer, 5'-TCTCTCAGTCAACGCCTCT-3'; and 3' primer, 5'-ATCCAGGATGGCCACTTCTT-3'. The amplification yielded a 299-bp DNA product corresponding to fragment 1801–2099 according to the published sequence of the NIS gene (4).

Primer oligonucleotides for the Tg gene were: 5' primer, 5'-AGGGAAACGGCCTTTCTGAA-3'; and 3' primer, 5'-GTGGAGAAGACGACGATTTC-3'. The amplification yielded a 408-bp DNA product corresponding to fragment 152–560 according to the published sequence of the gene (10).

Primer oligonucleotides for the TPO gene were: 5' primer, 5'-ACTGCACACGCTGTGGCTGC-3'; and 3' primer, 5'-TGCAGTTTGGCTGGTCTTGC-3'. The amplification yielded a 434-bp DNA product corresponding to fragment 1299–1733 according to the published sequence of the gene (11).

The Tg and the TPO primers spanned exon-intron junctions of the genes to exclude the possibility of genomic DNA contamination. For the same purpose, amplification of the NIS gene was performed after including a mock RT sample (by omitting the reverse transcriptase in the cDNA synthesis reaction), because the exon-intron organization of the NIS gene was published after these experiments were performed (12). All primers were obtained from Genosys (Cambridge, UK).

Dot blot

For dot blot hybridization of both normal and tumor thyroid tissue total RNAs with the labeled 1–2046 NIS rat probe, we used the technique previously described (8). The 1–2046 NIS rat probe was obtained by EcoRI-HindIII digestion of the full-length rat NIS cDNA (3). A murine actin probe (13) was used to ascertain equal RNA loading.

	Results

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Tg, TPO, and NIS messenger RNA (mRNA) expression

Normal thyroid tissues obtained from peritumoral thyroid areas showed, after amplification, a band of 408 bp representing the Tg transcript, a 434-bp band representing the TPO transcript, and a 299-bp band representing the NIS transcript (data not shown). Figure 1 shows the results in some of the tumors examined. All tumoral tissues except one anaplastic carcinoma presented the Tg and TPO transcripts, indicating the integrity of the mRNA and cDNA used in the experiments. Five of 19 papillary thyroid cancer tissues (no. 4, 6, 11, 14, and 15, Table 1) did not express the NIS transcript, suggesting that a reduction of iodide trapping in these tumors may be a consequence of the loss of NIS expression. The NIS transcript was not detected in one of five follicular thyroid cancers (no. 22, Table 1). In the two anaplastic tumors, NIS symporter mRNA was only barely detected in one case.

View larger version (51K): [in this window] [in a new window]   Figure 1. Presence of NIS, Tg, and TPO RNA in thyroid tissues. Agarose gel electrophoresis of PCR-amplified DNA of NIS (upper panel), Tg (medium panel), and TPO genes (lower panel). Lane 1, DNA mol wt marker XIV (Boehringer Mannheim). Lane 2, cDNA of human thyroid cells in primary culture (positive control). Lane 3, cDNA from mock RT samples (see Materials and Methods; negative control). Lanes 4–6, Tumor, normal, and metastasis cDNA, respectively, of a patient with papillary carcinoma. Lane 7, cDNA of a patient with anaplastic carcinoma. Lane 8, cDNA of a patient with follicular carcinoma. The expected bands are indicated by black arrows.

Dot blot analysis of NIS mRNA

In two cases (no. 17 and 18, Table 1) we evaluated by dot blot analysis the relative abundance of NIS mRNA in the nonmalignant thyroid tissue, the primary papillary tumor and its lymph node metastases. A slight, but not significant, decrease in NIS gene expression was observed in the primary cancer of one patient (no. 17) compared with that in the normal adjacent thyroid tissue. In contrast, in both patients, NIS gene expression was significantly reduced in the metastatic tissue (3- to 5-fold) compared to that in either normal or primary cancer tissues (Fig. 2). A murine actin probe (13) was used to ascertain equal RNA loading (Fig. 2).

View larger version (43K): [in this window] [in a new window]   Figure 2. Dot blot hybridization of normal (N), tumoral (T), and metastatic (LM) tissue RNA of two patients with thyroid papillary carcinoma. In panels A and C, total RNA was hybridized with labeled iodine carrier cDNA (EcoRI-HindIII, 1–2046 fragment of rat NIS gene; see Materials and Methods). In panels B and D, total RNA was hybridized with labeled murine actin probe to ascertain equal RNA loading.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The functional integrity of the iodine transport system in thyroid cancer cells is essential to assure an uptake of radioiodine high enough to detect and eradicate the neoplastic thyroid tissue. In the present study the expression of the NIS gene was investigated by RT-PCR in a series of thyroid tumors of different histotypes. Considering the limitations of RT-PCR as a quantitative method, we could evaluate only the presence or absence of NIS transcript in our series of tumors. In 24 differentiated carcinomas, we found a loss of expression of the iodide symporter gene in 6 primary thyroid tumors. On the contrary, all 24 tumors expressed both Tg and TPO genes. Molecular mechanisms may differently affect the expression of the NIS, Tg, TSH receptor, and TPO genes, or a different pattern of sensitivity may occur after oncogenic transformation. The absence of the NIS function, by reducing iodide uptake, may confer to these tumor cells a proliferative advantage due to the loss of the iodine autoregulation process (15). The absence of NIS mRNA signal, however, is not restricted to the malignant phenotype, because we found one cold benign follicular adenoma carrying this defect.

In our small series, four of eight DTC patients with distant metastases and negative posttherapeutic TBS presented with a lack of NIS gene expression in the primary cancer (no. 6, 11, 14, and 22). At least in these cases, therefore, the absence of NIS appears intrinsic to the primary transformed thyroid cell and not acquired in the metastatic tissues through a further dedifferentiation during the tumor progression process. If these data are confirmed in a larger unselected series of DTC patients, this finding may have a clinical impact. When the loss of NIS gene expression is found in the primary tumor, the tumor cells will not pick up ¹³¹I, and in the case of elevated serum Tg levels, ¹³¹I TBS performed even with a high dose will be negative. In such cases, alternative tools to detect metastases, such as octreoscan (16), positron emission tomography scan (17), or conventional imaging modalities, may be used. In cases with negative TBS in the presence of NIS expression in the neoplastic tissue, other mechanisms are responsible for the failure to concentrate radioiodine. Among these mechanisms, a defect (intrinsic and/or acquired) in the iodide symporter protein structure or activation or an alteration in iodide organification may be involved. The function of the iodide symporter system, in fact, may require the full expression of the mature iodide transporter protein in the cellular plasma membrane.

On the contrary, a decrease in NIS gene expression in lymph node metastases compared to those in both normal thyroid tissues and primary tumor was detected. This result may be a consequence of cancer progression and malignant metastatic cell dedifferentiation. In conclusion, as the iodide symporter system plays a critical role in thyroid tumorigenesis, analysis of its mRNA expression may offer useful information for the management of and therapeutic approach to DTC patients, especially in the presence of metastases.

	Acknowledgments

 
We thank Dr. R. Vigneri (University of Catania) for his continued support during the study.

	Footnotes

 
¹ This work was supported by the Associazione Italiana per la Ricerca sul Cancro (to S.F.), the Association pour la Recherche sur le Cancer, the Ligue Nationale Française contre le Cancer and Electricitè de France (to H.G.S.), and the leg Paulette Jamet (to M.S.). This study is part of the Galileo Program.

Received December 23, 1997.

Revised March 19, 1998.

Accepted April 7, 1998.

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