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Original Studies |
Departments of Clinical Biology (V.L., J.M.B., L.L.), Pathology (B.C.), Biostatistics (C.M.), and Nuclear Medicine (M.S.), 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: Prof. M. Schlumberger, Institut Gustave-Roussy and University Paris-Sud, 39 rue Camille Desmoulins, 94805 Villejuif, France.
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Abstract |
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NIS expression was decreased in 40 of 43 thyroid carcinomas (10- to 1200-fold) and in 20 of 24 cold adenomas (2- to 700-fold); it was increased in toxic adenomas and Graves’ thyroid tissues (up to 140-fold). TPO expression was decreased in thyroid carcinomas, but was normal in cold adenomas; it was increased in toxic adenomas and Graves’ thyroid tissues. Tg expression was decreased in thyroid carcinomas, but was normal in the other tissues. TSH-R expression was normal in most tissues studied and was decreased in only some thyroid carcinomas.
In thyroid cancer tissues, a positive relationship was found between the individual levels of expression of NIS, TPO, Tg and TSH-R. No relationship was found with the age of the patient. Higher tumor stages (stages >I vs stage I) were associated with lower expression of NIS (P = 0.03) and TPO (P < 0.01).
Expression of the Glut1 gene was increased in 1 of 24 adenomas and in 8 of 43 thyroid carcinomas. In 6 thyroid carcinoma patients, 131I uptake was studied in vivo; NIS expression was low in all samples; 3 patients with normal Glut-1 gene expression had 131I uptake in metastases, whereas the other 3 patients with increased Glut-1 gene expression had no detectable 131I uptake.
In conclusion, this study shows 1) a reduced expression of NIS gene in most hypofunctioning benign and malignant thyroid tumors; 2) a differential regulation of the expression of thyroid-specific genes; 3) an increased expression of Glut-1 gene in some malignant tumors that may suggest a role for glucose derivative tracers to detect in vivo thyroid cancer metastases by positron emission tomography scanning.
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Introduction |
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Indeed, most malignant thyroid tumors appear hypofunctioning (cold nodule) on thyroid scintiscan, indicating an impaired radioiodine-trapping ability. Abnormalities in iodine thyroidal metabolism may hamper the diagnostic and therapeutic use of radioiodine in DTC patients. In fact, 131I uptake by these tumoral thyroid tissue is always lower than that in its normal counterpart and is not detectable in one third of patients with metastases. On the other hand, serum Tg is detectable in most DTC patients with persistent or recurrent disease, indicating that the majority of DTC retains the capability to synthesize Tg. Its concentration increases after thyroid hormone withdrawal even in the absence of detectable 131I uptake, demonstrating that these neoplastic tissues are able to respond to TSH stimulation (21, 22, 23).
In in vitro studies, multiple biochemical abnormalities have been found, including a low intrathyroid concentration of iodine, a low degree of iodination of Tg, and a low rate of thyroid hormone synthesis (11, 12). The biological activity of peroxidase, a key thyroid enzyme in the iodide organification process, although normal in benign cold adenomas, was decreased in thyroid carcinomas (10, 15), whereas TSH-R were detected in most differentiated thyroid tumors, including thyroid carcinomas (8, 14, 19).
These studies suggest that abnormalities in the iodine transport mechanism and in the peroxidase system account for most of the biochemical defects observed in these tumors. However, only a single or a few functional parameters have been previously examined in small series of tumor samples, therefore avoiding the understanding of the whole spectrum of biochemical defects in these tumors. These findings have raised a number of as yet unanswered questions: 1) whether thyroid-specific proteins in tumor tissues are altered by genetic or epigenetic modifications; 2) whether and to what extent multiple changes in gene expression are present and associated with the neoplastic phenotype; 3) whether differentially expressed genes were associated with a particular thyroid tumor phenotype; and 4) whether the appearance of molecular abnormalities is restricted to malignant tissues.
To address these issues, we analyzed the expression of the four functional parameter-encoding genes, including NIS, TPO, Tg, and TSH-R, in a large number of well characterized microdissected tissues. Furthermore, due to the clinical importance of positron emission tomography (PET) scan in the work-up of malignant thyroid tumors (24), we also studied the expression of the glucose transporter type 1 (Glut1) gene (25, 26, 27). To compare gene expressions in different samples, a recent kinetic quantitative PCR method, based on the fluorescent TaqMan (Perkin Elmer Corp., PE Applied Biosystems, Foster City, CA) methodology and real-time measurement of fluorescence, was used (28).
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Materials and Methods |
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Tissue samples were selected after histological examination and classified according to WHO recommendations (29). This study was performed in accordance with protocols previously approved by the local human studies committee.
Five thyroid samples were obtained from patients with Graves’ disease; eight samples were obtained from patients with toxic adenoma as demonstrated by undetectable serum TSH levels and increased 131I uptake in the nodule on thyroid scintigraphy. Five samples, classified as hyperplastic thyroid tissues, were obtained from non macroscopically tumoral areas of euthyroid multinodular goiters, with both hypo- and hyperfunctioning areas on thyroid scintigraphy. Twenty-four samples were obtained from benign thyroid follicular adenomas that appeared hypofunctioning on thyroid scintigraphy.
Forty-three samples were obtained from DTC. There were 5 poorly differentiated and widely invasive follicular carcinomas and 38 papillary thyroid carcinomas. Poorly DTC occurred in 2 males and 3 females with a mean age of 46.6 yr (SD, ±13.5 yr). According to the TNM classification (30), 3 were classified as stage I, 1 as stage II, and 1 as stage IV. Papillary thyroid carcinomas occurred in 5 males and 33 females with a mean age of 41.9 yr (SD, ±15.4 yr). According to the TNM classification, 24 (63%) were classified as stage I, 1 as stage II, 11 as stage III, and 2 as stage IV. Only 6 cancer patients had lymph node or distant metastases after initial surgical treatment that permitted us to assess in vivo the capability of the tumor tissue to take up 131I.
Finally, paired samples of both normal and tumoral thyroid tissues were obtained in five patients with an unifocal papillary carcinoma; normal thyroid samples, taken from the contralateral lobe, were used as calibrator materials in the real-time PCR analysis. 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.
Determination of messenger ribonucleic acid (mRNA) levels using real-time PCR
Tissue specimens were frozen at -80 C in isopentane and stored in liquid nitrogen before use. Total RNA was isolated using the DNA/RNA extraction Midi kit according to the manufacturer’s instructions (QIAGEN, Hilden, Germany). The quality of RNA samples was assessed by electrophoresis through denaturing agarose gels and staining with ethidium bromide, and the 18S and 28S RNA bands were visualized under UV illumination. The extraction yield was quantified spectrophotometrically. Oligonucleotide primers and TaqMan probes were designed to be intron spanning using the computer program Primer Express (Perkin Elmer Corp., PE Applied Biosystems). Sequences were obtained from GenBank databases as follows: NIS (AI261687), TPO (M17755), Tg (X05615), TSH-R (M73747), and Glut1 (M28384). Oligonucleotides primers and probes were purchased from Perkin Elmer Corp. PE Applied Biosystems. The nucleotide sequences of both primers and probes are available on request.
One microgram of total RNA for each sample was reverse transcribed in a 20-µL volume reaction using 50 U Moloney murine leukemia virus reverse transcriptase, 20 U ribonuclease inhibitor (Perkin Elmer Corp. PE Applied Biosystems), 1 mmol/L dA/T/C/G (Amersham Pharmacia Biotech, Uppsala, Sweden), 5 mmol/L MgCl2, 10 mmol/L Tris-HCl (pH 8.3), 10 mmol/L KCl, and 50 pmol/L random hexamers (Perkin Elmer Corp. PE Applied Biosystems). All 95 RNA samples included in the study as well as a negative RT control were performed using a common RT mixture, aliquoted in 96 tubes. The complementary DNAs (cDNAs) were then diluted 1:20 in nuclease-free H2O (Promega Corp., Madison, WI).
Quantitative PCR reaction was carried out in 96 sample tubes/assay, using a cDNA equivalent of 20 ng/total RNA·50 µL/tube using the TaqMan PCR core reagent kit according to the manufacturer’s instruction: 1 x buffer A, 5 mmol/L MgCl2, 200 µmol/L dA/C/G, 400 µmol/L dU, 1.25 U AmpliTaq Gold DNA polymerase, 2.5 unit uracil N-glycosylase, 100 mmol/L TaqMan probe, and 200 mmol/L of each primer. PCR was developed on the ABI Prism 7700 Sequence Detector (Perkin Elmer Corp. PE Applied Biosystems). For each target, a unique PCR master mix, aliquoted in 96 samples, allowed the amplification in batch of all 95 samples plus the negative RT-PCR control. PCR were processed through 40 cycles of 2-step PCR, including 15 s of denaturation at 95 C and 1 min of annealing-elongation at 60 C, using the standard protocol of the manufacturer. The monitoring of negative controls for each target showed an absence of carryover. Additionally, 1 of each type of amplicon, corresponding to each target, was migrated on agarose gel electrophoresis and showed a unique band at the expected size. Direct sequencing of PCR products certified the specificity of PCR reactions.
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. Primers and probes for 18S RNA were purchased from Perkin Elmer Corp. PE Applied Biosystems. The mRNA content for each target was simultaneously determined in 96 samples, including the 10 paired normal/tumoral samples, in a 1-run assay.
Statistical methods
The expressions of NIS, TPO, Tg, TSH-R, and Glut1 genes detected in each of the five histological groups were compared with their expressions in normal samples. Regarding cold adenomas and carcinomas, expressions of mRNAs were compared using t test, and relationships between these expressions were studied using Spearman’s rank order correlation coefficient for each of the groups. Finally, relationships were sought in carcinomas between the expression of mRNAs and age at the time of surgery, and tumor stage using the TNM classification (stages >1 vs stages >1). The significance level was set at 5%.
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Results |
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To validate the real-time PCR method, standard curves for each of
the five targets and ribosomal RNAs were constructed from cDNA obtained
from a normal thyroid tissue serially diluted in nuclease-free
H2O. Figure 1
shows the
real-time PCR standard curve for the NIS gene. Comparative
amplification curves of the five targets plus ribosomal 18S RNAs
obtained for a paired normal/tumoral sample are presented in Fig. 2. Similar efficiencies of standard
curves, as determined by the slope of the standard curve for each
parameter, allowed us to quantify gene expression profiles in the
various thyroid specimens using the comparative threshold cycle method
according to the manufacturer’s instructions. The calibrator was
constituted from one sample of normal tissue; it was used as the
1x sample and all other levels were expressed as an
x-fold difference relative to the calibrator. The
coefficient of intraassay variation (n = 8) was determined for
each parameter at two comparative threshold cycle values and was less
than 1%, except for 18S RNA (1.6%).
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Mean and median values obtained for the five normal tissues were
similar, suggesting that there is no wide variations in the expression
of each of the five genes analyzed (Table 1).
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In euthyroid hyperplastic glands, the mean expression of NIS mRNA was also increased compared to that in normal thyroid tissues, but to a lesser extent than in the previous group. The expressions of TPO, Tg, TSH-R, and Glut1 transcripts were normal.
Thyroid adenomas and carcinomas
Expression of the 4 thyroid-specific genes was detected in all tissue samples, but with a wide range of variability. In cold benign adenomas, the expressions of Tg, TSH-R, and TPO genes overlap the mRNAs values detected in normal thyroid tissue. Conversely, levels of NIS mRNAs, although in the normal range in 4 samples, were 2- to 700-fold lower in 20 samples, indicating a peculiar and specific alteration.
More extensive alterations were detected in malignant thyroid tissues. NIS mRNA expression, although normal in 3 samples, was 10- to 1200-fold lower (median, 100-fold) in the other 40 samples. Furthermore, carcinoma cells display reduced levels of TPO by 5- to 500-fold and of Tg mRNAs by 2- to 300-fold. Interestingly, the mean expression of TSH-R transcripts was normal in most tumors and was decreased by more than 10-fold in only 3 samples.
The Glut1 gene was expressed at a level similar to that in normal tissues, except in one adenoma and in eight thyroid carcinomas that displayed a 3- to 10-fold increase.
Among carcinomas, no difference in the levels of expression of the
various transcripts was found between papillary and follicular poorly
differentiated histological types (Fig. 3).
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We next examined whether the reduced expression of iodide symporter gene and the in vivo radioiodine uptake by thyroid neoplastic cells were related. Thus, in six thyroid cancer patients with persistent or recurrent disease after initial treatment, 131I uptake could be assessed in vivo. Indeed, low NIS mRNA expression was found in all six tumor samples; however, Glut1 gene expression was normal in the three patients with 131I uptake in metastases, whereas it was increased in the three patients in whom no detectable uptake was found, even after the administration of a large amount (100 mCi) of 131I.
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Discussion |
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The use of quantitative expression analysis based on real-time analytical RT-PCR offers several advantages over other current quantitative methods. It proved to be a rapid, reliable, and highly sensitive method to quantify the simultaneous expression levels of a large number of genes (31, 32).
Together, our observations are in close agreement with those of previous studies (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20), but also permit an extension of these findings by demonstrating that altered gene expression may play a major role in the bioactivity of thyroid-specific proteins.
In Graves’ thyroid tissues and in toxic adenomas with high thyroid uptake of radioiodine, NIS expression was increased. This is in accordance with the stimulatory effect of the TSH pathway on NIS expression (33). Expression of TPO was also increased, although at a lesser degree, and this is consistent with an increased synthesis of thyroid hormones. Tg mRNA expression was not significantly increased, indicating that it is less sensitive to thyroid stimulation. This is in sharp contrast with the high serum Tg levels observed in most thyrotoxic patients and with the well established stimulatory effect of TSH on serum Tg level. Similarly, expression of TSH-R was not significantly increased. In hyperplastic thyroid tissues, the levels of expression of NIS, TPO, and other transcripts studied were similar or slightly higher than those in normal thyroid glands. This is in agreement with the patchy distribution of radioiodine uptake, with hypo- and hyperfunctioning areas on thyroid scintiscan. It is also in close agreement with the currently available data on the pathogenesis of multinodular goiter (16).
In all samples of benign cold adenomas and carcinomas, all genes were expressed. However, NIS mRNA levels were decreased and at similar levels in both adenomas and carcinomas. In contrast to a previous report (17), NIS gene expression, although normal in three samples of thyroid carcinoma, was never found to be increased. Our data are in agreement with previous reports using RT-PCR (18), RT-competitive PCR (34), and immunohistochemistry (19, 20). A striking difference is the much lower expression of TPO mRNA in thyroid carcinomas than in cold adenomas. This is in accordance with previous biochemical studies that showed decreased peroxidase activity in most DTC and its absence in about 50% of DTC (10, 15). Furthermore, expression of Tg was lower in thyroid carcinomas than in cold adenomas. The presence of Tg was indeed demonstrated in most DTC by immunohistochemistry or RT-PCR. However, its concentration was lower than that in normal tissue and was lowest in poorly differentiated histotypes (8, 13, 14). In thyroid cancer tissue, Tg was poorly iodinated, and hormonal production of T3 and T4 was rarely observed (11, 12, 21). The present study suggests that its poor degree of iodination may be related to defects in both the iodine-trapping ability and the iodination process. The low level of both TPO and Tg mRNA expression may also explain the short biological intrathyroidal half-life of 131I observed in most DTC. Therefore, the low basal level of expression of NIS and Tg mRNA in cancer tissues in euthyroid conditions confirms the need for high serum TSH levels to stimulate 131I uptake and Tg production (21, 23). Indeed, this is supported by the finding that the majority of DTC transcribed the TSH-R gene, in agreement with previous biochemical and immunohistochemical studies (8, 13, 14). Mean mRNA expression of TSH-R was only slightly decreased, to a much less extent than that of other mRNAs even in samples of poorly DTC. In thyroid carcinomas, the levels of expression of these four mRNAs (NIS, TPO, Tg, and TSH-R) were strongly correlated, indicating multiple defects in the hormonal synthesis. This finding also suggests that control mechanisms are deficient in most carcinomas. Identification of the mechanisms responsible for these differentially expressed genes and their associated protein functions will provide insight into the regulatory pathways in thyroid transformed cells. The levels of expression of NIS, TPO, and Tg transcripts were much lower than that of TSH-R mRNA, suggesting that other defects in control mechanisms, beside the TSH-R pathway, may exist. The differential pattern of expression as well as the observed discrepancy between adenomas and carcinomas regarding the levels of NIS and TPO mRNAs rule out the possibility that a unique alteration, such as that of one of the thyroid-specific transcription factors (TTF1, TTF2, and Pax-8), are exclusively responsible for the abnormalities in thyroid gene expression (35, 36, 37, 38).
Levels of expression of mRNAs decreased with higher tumor stages. This suggests an accumulation of defects with thyroid tumor progression. This is also in close agreement with clinical findings. 131I uptake in metastases is more frequently observed and, when present, is more important in patients with small than in those with large metastases (22).
Finally, Glut1 mRNA expression may provide new insights into the physiopathology of neoplastic follicular thyroid cells. Increased expression of Glut1 is associated with neoplastic transformation of thyroid cells (25, 26, 27). In in vivo studies with PET scanning, the uptake of 18F-fluorodeoxyglucose was more frequently found in poorly DTC with no demonstrable 131I uptake (24). Our study suggests that among DTC with a constantly low level of NIS mRNA expression, the level of Glut1 transcripts may help to differentiate tumors with 131I uptake, with normal Glut1 expression, from those with no demonstrable 131I uptake and expressing high levels of Glut1 transcripts, which may have high 18F-fluorodeoxyglucose uptake on PET scan. Thus, our finding may have important clinical implications by providing the rationale and the biological basis for a role for the PET scan in thyroid cancer management.
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Acknowledgments |
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Footnotes |
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Received April 9, 1999.
Revised June 4, 1999.
Accepted June 21, 1999.
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