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Original Studies |
Molecular Thyroid Research Unit Medizinische Klinik (C.S., W.J., A.E.F.), and Department of Legal Medicine (W.E.), Klinikum Innenstadt, Ludwig-Maximilians-Universität, 80336 München, Germany
Address all correspondence and requests for reprints to: A. E. Heufelder, M.D., Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians-Universität, Ziemssenstr. 1, 80336 München, Germany. E-mail: u7g11av{at}mail.lrz-muenchen.de
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Abstract |
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Introduction |
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The thyroid gland shares its capacity to actively accumulate iodide (I-) with several other tissues, including salivary gland, gastric mucosa, lactating mammary gland, choroid plexus, and ciliary body of the eye (1). Additionally, several normal and abnormal tissues, such as nonlactating mammary gland, lacrimal gland, nasopharynx, thymus, skin, placenta, inflammatory lung tissue, and lung carcinoma (7, 8, 9, 10, 11, 12, 13), have been reported to take up radioiodine. The iodide transport system in these extrathyroidal tissues reveals several functional similarities to its thyroid counterpart, such as inhibition of iodide transport by thiocyanate and perchlorate (1). By contrast, extrathyroidal iodide transport is not regulated by TSH, and extrathyroidal tissues are not able to organify the accumulated I- (1). Our current study was designed to evaluate, using Northern blot analysis and RT-PCR amplification followed by Southern hybridization, the distribution and abundance of hNIS gene expression in a broad range of human extrathyroidal tissues. Further, we investigated whether the lower levels of iodide transport and concentrating activity in extrathyroidal tissues may be caused by expression of an altered hNIS protein structure. To this purpose, the entire coding region of the hNIS gene was amplified and cloned from parotid gland, mammary gland, and gastric mucosa and was compared with the recently published thyroid-derived hNIS gene sequence.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Total RNA was isolated from human thyroid tissue, and
single-stranded oligo-(dT)-primed cDNA was generated. The cDNA probes
for Northern blot analysis were generated by PCR using a pair of hNIS
gene-specific primers (sense primer: residues 1184–1202; antisense
primer: residues 1648–1667). To facilitate subcloning of PCR-products,
primers were designed to contain recognition sites for the restriction
enzymes EcoRI and BamHI, respectively. Following
amplification, PCR products were digested with BamHI and
EcoRI (at 37 C, for 1.5 h) and were separated on an
ethidium bromide-stained agarose gel. The band of interest was excised
and purified using the QIAquick Gel Extraction Kit (Qiagen, Hilden,
Germany). This fragment was ligated overnight at 16 C into the
BamHI/EcoRI-sites of the DNA-plasmid
pBluescript-SK II (-) (Stratagene, Heidelberg, Germany). Transfection
of competent Escherichia coli XL1-blue cells was performed
by electroporation using the Easyject Plus Electroporation System
(Eurogentec, Seraing, Belgium). Clone phNIS-1 was obtained and plasmid
DNA was purified with Qiagen-tip 20 (Qiagen), followed by sequencing
using Sequenase version 2.0 (U.S. Biochemicals, Bad Homburg, Germany)
and [
-35S]dATP for labeling. For Northern blot
analyses, the hNIS-1 fragment was cut out of the vector, resolved on an
ethidium bromide-stained agarose gel, and purified using QIAquick Gel
Extraction Kit (Qiagen).
Northern blot analysis of hNIS messenger RNA (mRNA)
Total RNA was isolated from various human tissue specimens that
had been obtained at surgery, endoscopy, or autopsy, and they were
immediately frozen in liquid nitrogen. Thereafter, RNA was
electrophoresed on a 1% agarose gel containing 2 M
formaldehyde, and was transferred overnight in 20 x saline-sodium
citrate (SSC) to a positively charged nylon membrane (Qiagen). In
addition, multiple tissue Northern blots were obtained from Clontech
Laboratories, Inc. (Heidelberg, Germany). The hNIS-gene specific
cDNA-fragment was radiolabeled with
[-32P]deoxyadenosine-5'-triphosphate by random priming
(Amersham, Braunschweig, Germany), and was used as a hybridization
probe. Blots were prehybridized at 42 C in a hybridization mix
containing 50% formamide for 6 h, followed by hybridization at 42
C for 16 h. Blots were then rinsed four times in 2x SSC/0.05% SDS
at room temperature for 10 min, and twice in 0.1x SSC/0.1% SDS at 50 C
for 20 min, respectively. Exposures were made at -80 C for 48 h
using Kodak X-OMAT AR film sigma, (Deisenhofen, Germany). To strip off
the hNIS cDNA probe, blots were treated in 0.5% SDS at 95 C for 10 min
and were reprobed with a human ß-actin cDNA probe to monitor RNA
integrity and quantity. Computer-assisted densitometric analysis of
band intensities was performed, and hNIS-measurements were normalized
for ß-actin signal intensity.
RNA preparation and PCR amplification
Total RNA was isolated from a broad range of normal human tissues by the modified acid guanidinium thiocyanate-phenol-chloroform method, according to Chomczynski and Sacchi (14), using the RNeasy Midi Kit (Qiagen). Pooled mRNA from various types of salivary glands was purchased from Clontech. Single-stranded oligo (dT)-primed cDNA was generated using Superscript II reverse transcriptase (Life Technologies, Eggenstein, Germany). Oligonucleotide primers, used for analysis of hNIS RNA expression, were CCC GGA TCC GCT GGC CCT GCT CAT CAA (nucleotides 1184–1202: sense strand) and CCC GAA TTC GCA GGC CGG CAG GAA CAT TC (nucleotides 1648–1667: antisense strand) (cDNA sequences underlined). These primers should generate a product that is 483 bp in length. Amplification was performed with 3 µL of each cDNA template, 50 pmol of each primer in 5 µL 10 x reaction buffer (Boehringer Mannheim, Mannheim, Germany), and 2 U Taq DNA polymerase (Boehringer Mannheim) in a final vol of 50 µL. The amplification reaction was for 30 cycles, and each cycle consisted of 94 C for 1 min (denaturation), 58 C for 2 min (annealing), and 72 C for 2 min (extension), followed by a final 10 min elongation at 72 C.
To control integrity of the cDNA templates and to rule out DNA contamination carried over in the samples, all templates were amplified with primers that span an intron of the ß-actin gene. Oligonucleotide primers for ß-actin amplification were TGA CGG GGT CAC CCA CAC TGT GCC CAT CTA (nucleotides 1038–1067: sense-strand) and CTA GAA GCA TTG CGG TGG ACG ATG GAG GG (nucleotides 1876–1905: antisense-strand). The expected ß-actin product from a cDNA template is 661 bp. Reaction conditions were as above. In addition, to rule out the possibility of illegitimate transcription, all cDNA samples were amplified with a pair of intron-spanning primers designed to amplify 683-bp and 512-bp fragments of the human thyroglobulin gene. Oligonucleotide primers for thyroglobulin amplification were GGC CTG TGT CCC ATG TCC TG (sense strand) and TGG CTC CTG AGG CTG AGA AC (antisense strand) (15). All amplifications were run at cycle numbers that ensured linear amplification (30 cycles for NIS and thyroglobulin amplifications and 25 cycles for ß-actin amplification).
Southern blot analysis
Ten microliters of each PCR product were separated on 1% agarose gels, stained with ethidium bromide, and transferred to positively charged nylon membranes (Qiagen). Hybridization was carried out with a digoxigenin (DIG)-labeled internal hNIS-specific oligonucleotide probe (nucleotides 1460–1477). Membranes were washed with buffer 1 (0.1 mol/L maleic acid, 0.15 mol/L NaCl; pH 7.5) containing 0.3% (vol/vol) Tween-20 and then incubated in buffer 2 [1% blocking solution (Boehringer Mannheim) in buffer 1] for 30 min. After incubation in anti-DIG-alkaline phosphatase-conjugate (dilution 1:10.000 in buffer 2) for 30 min, membranes were washed twice in buffer 1 containing 0.3% Tween-20 and then equilibrated in buffer 3 (0.1 mol/L Tris-HCl, 0.1 mol/L NaCl, 50 mmol/L MgCl2). Membranes were then incubated in lumigen-PPD (dilution 1:100 in buffer 3) for 5 min and exposed to x-ray film for 10 min.
Amplification and subcloning of hNIS-specific cDNA from extrathyroidal tissues
Total RNA from parotid gland and gastric mucosa from normal
human donors was prepared as described above. mRNA from mammary gland
was purchased from Clontech. Single-stranded oligo-(dT)-primed cDNAs
were generated and used as templates for cyclic thermal amplification
with the EXPAND High Fidelity PCR System (Boehringer Mannheim). This
system’s proofreading activity markedly decreases the possibility of a
point mutation caused by Taq amplification. cDNA fragments
representing the entire coding region of the hNIS gene were then
generated by PCR using three overlapping pairs of hNIS-specific primers
(hNIS-M1-hNIS-M6). Table 1
illustrates
nucleotide sequences of these primers, as well as their localizations
and orientations, respectively. To facilitate subcloning of specific
PCR products, primers were designed to contain recognition sites for
the restriction enzymes EcoRI and BamHI,
respectively. Restriction hydrolysis of the resulting PCR products
using BamHI and EcoRI, isolation, ligation into
DNA-plasmid pBluescript-SK II (-), and transformation were performed
as described above. Fig. 1 shows a
schematic illustration of the amplification and cloning strategy.
Plasmid DNA of at least two independent cDNA clones, obtained from each
tissue, were isolated and sequenced using the RR DyeDeoxy Terminator
Cycle Sequencing Kit (Perkins Elmer Applied Biosystems, Weiterstadt,
Germany).
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Results |
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hNIS mRNA expression profiles were examined by high-stringency
Northern blot analysis using a 32P-labeled hNIS-specific
cDNA probe. Abundant hNIS mRNA expression was detectable as a single
species of approximately 4 kb in thyroid gland. In addition, a weaker
hNIS mRNA signal was also detectable in parotid gland (Figs. 2 and 3).
Even after film exposure for 1 week, strong ß-actin mRNA signals (but
not an hNIS mRNA signal) were detected in brain, thymus, heart,
stomach, small intestine, colon, lung, liver, skeletal muscle, kidney,
spleen, placenta and peripheral blood leucocytes, and in a variety of
endocrine tissues, such as pancreas, adrenal gland, prostate, testis,
and ovary (data not shown).
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For analysis of low levels of hNIS gene expression in small
samples obtained from various normal human tissues, total RNA was
prepared from freshly frozen tissue specimens, followed by RT-PCR with
a pair of hNIS-specific oligonucleotide primers (Figs. 4 and 5,
top). To monitor cDNA integrity and quantity, all samples
were coamplified with a pair of human ß-actin primers (Figs. 4 and 5,
middle). Moreover, to rule out the possibility of
contaminating DNA and illegitimate transcription, all cDNA samples were
coamplified with a pair of primers specific for human thyroglobulin.
Human thyroglobulin-specific transcripts were detected in thyroid
tissue but not in any other cDNA sample examined. hNIS-specific
transcripts were confirmed by Southern hybridization using a
DIG-labeled internal hNIS-specific oligonucleotide probe (Figs. 4 and 5, bottom). RT-PCR and Southern hybridization revealed hNIS
gene expression in thyroid gland, salivary gland, parotid gland,
submandibular gland, pituitary gland, pancreas, testis, mammary gland,
gastric mucosa, prostate and ovary, adrenal gland, heart, thymus, and
lung. By contrast, hNIS transcripts were not detected in normal orbital
fibroblasts, colon, and nasopharyngeal mucosa (Figs. 4 and 5).
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To investigate whether the reduced capacity to trap iodide in extrathyroidal tissues, compared with thyroid gland, may be caused by an altered primary structure of hNIS cDNA, single-stranded cDNAs were generated from RNA derived from parotid gland, mammary gland, and gastric mucosa. To facilitate PCR cloning and sequencing, amplifications were performed using three overlapping NIS-specific pairs of primers designed to encompass the entire coding region of the hNIS gene. PCR products of appropriate lengths (654 bp, 775 bp, and 730 bp, respectively) were obtained from each tissue, followed by subcloning and sequencing of at least two independent cDNA clones derived from each tissue. Nucleotide sequences of hNIS cDNAs, expressed by each of the three extrathyroidal tissues, revealed full identity with the recently published human thyroid-derived NIS cDNA (5). No point mutations, insertions, deletions, or evidence of alternative splicing were found.
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Discussion |
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Whole-body scintigraphy with radioiodine-131, an important diagnostic test in the management of patients with differentiated thyroid cancer, has revealed false-positive uptake in a significant number of cases. Radioiodine uptake has been noted in a variety of normal and abnormal extrathyroidal tissues, such as nonlactating mammary gland (8), lacrimal gland (9), nasopharynx (10), thymus (11), skin (13), placenta (13), pleuropericardial (7) and renal cysts (10), inflammatory lung disease (10), Meckel’s diverticulum (10), ovarian cystadenoma (10), meningeoma (10), and lung carcinoma (12). Although iodide uptake by these extrathyroidal tissues may result from nonspecific iodide accumulation, our detection of significant quantities of hNIS gene expression in thyroid gland, salivary glands, thymus, pituitary gland, pancreas, testis, mammary gland, and gastric mucosa, and of lower degrees of NIS gene expression in prostate, ovary, adrenal gland, lung, heart, and nasopharyngeal mucosa suggests that iodide transport in some of these tissues may be a specific property conferred by the expression of NIS. Recently, in support of our study, Smanik and colleagues (6) have detected hNIS expression in breast, colon, and ovary by RT-PCR, suggesting that hNIS may mediate the iodide uptake activity in both thyroid and these nonthyroid tissues. In contrast to their observation, perhaps because of variable levels of hNIS gene expression in different colon segments or interindividual differences in hNIS gene expression, we were not able to detect hNIS gene expression in colon.
Compared with the thyroid gland, iodide transport and concentrating activity is much lower in extrathyroidal tissues. Reduced iodide uptake activity in these tissues may result from expression of a hNIS protein with an altered primary structure. Recently, several hNIS gene mutations have been detected in patients with congenital hypothyroidism caused by an iodide transport defect (18, 19, 20). To examine whether an altered primary structure of NIS in extrathyroidal tissues may explain their diminished iodide uptake capacity, we determined the entire hNIS coding sequence in several extrathyroidal tissues. Our results demonstrate that, in extrathyroidal tissues, reduced iodide trapping activity does not seem to be caused by an altered NIS cDNA structure, because NIS coding sequences in tissues such as parotid gland, mammary gland, and gastric mucosa revealed full identity with thyroid hNIS cDNA. Moreover, no evidence of alternative splicing of NIS gene was found in the tissues analyzed. Because identical NIS proteins are encoded in thyroid tissue and extrathyroidal tissues, diminished iodide transport in extrathyroidal tissues may result from altered NIS gene transcriptional activity, perhaps as a consequence of altered promoter structure or function, or from altered NIS mRNA or protein turnover. Variable and lower NIS transcriptional activity in extrathyroidal tissues may be accounted for, at least in part, by thyroid-specific transcription factors that act on the NIS promoter to control NIS gene expression in the thyroid gland. Specific gene expression of thyroglobulin, thyroperoxidase, and TSH-receptor in the thyroid gland is well known to be regulated at the transcriptional level (21). Thyroid transcription factor 1 (TTF-1), a homeodomain-containing protein, has been found to bind to all three thyroid-specific promoters and to activate their transcriptional activity (22, 23). Recently, cloning and functional analysis of rat NIS gene has identified a binding sequence for TTF-1 within the rat NIS promoter region (16). These findings suggest that TTF-1 may be one of the factors capable of activating NIS gene expression in the thyroid gland, thus accounting for lower levels of NIS gene expression in extrathyroidal tissues. Further studies will address this hypothesis and examine the mechanisms of tissue-specific NIS gene expression.
Recently, several lines of evidence have identified hNIS as a potential autoantigen in autoimmune thyroid diseases. Serum obtained from a patient with Hashimoto’s thyroiditis, autoimmune gastritis, and rheumatoid arthritis was found to inhibit the chronic TSH-induced I- uptake by cultured dog thyrocytes, suggesting the presence of autoantibodies against hNIS in this patient’s serum (24). After cloning of rNIS, immunoblot analysis of sera from patients with Graves’ disease and patients with Hashimoto’s thyroiditis has indicated that autoantibodies against NIS are commonly detected in patients with autoimmune thyroid diseases (25). Interestingly, NIS autoantibodies in sera from patients with Hashimoto’s thyroiditis were found to inhibit iodide transport by thyrocytes (26). Moreover, Morris and colleagues (27, 28) have observed increased binding of IgG, from patients with autoimmune thyroid diseases, to several synthetic rNIS and hNIS peptides. Taken together, there is increasing evidence that sera from patients with Hashimoto’s thyroiditis and Graves’ disease contain antibodies that cross-react with rNIS and hNIS. Thus, NIS seems to represent a potential autoantigen that may play a role in the pathogenesis of autoimmune thyroid disease and associated autoimmune diseases. In fact, in various extrathyroidal tissues, such as gastric mucosa, salivary glands, and lacrimal gland, hNIS may act as a target antigen for T cells and cross-reacting autoantibodies, thus perhaps providing a link between autoimmune thyroid diseases and associated autoimmune diseases of other organ systems, such as autoimmune gastritis and Sjögren’s syndrome. Given the expression of hNIS mRNA in various endocrine and secretory glands that are common targets in autoimmune diseases, NIS protein expression in these tissues and its potential role as a shared autoantigen in the evolution of polyglandular autoimmune syndromes warrants further analysis. With the recent availability of specific antibodies generated against hNIS protein, these studies are now in progress.
Received November 19, 1997.
Revised January 28, 1998.
Accepted February 4, 1998.
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