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Divisions of Medical Sciences (K.B., C.J.M., L.A.T., N.J.L.G., J.C.W., M.C.S., J.A.F.) and Immunity and Infection (A.R.B.), University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom; and Department of Statistics (R.L.H.), University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom
Address all correspondence and requests for reprints to: Dr. K. Boelaert, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: k.boelaert{at}bham.ac.uk.
Abstract
Differentiated thyroid cancers are the most common endocrine cancers, but there are no reliable molecular markers of prognosis. Pituitary tumor transforming gene (PTTG) plays several potential roles in tumor initiation and progression, including regulating mitosis and stimulating expression of fibroblast growth factor (FGF)-2. Increased expression of PTTG has been demonstrated in follicular thyroid lesions, and expression of this oncogene has been identified as a potential prognostic marker in pituitary adenomas and colon carcinomas. We assessed the expression of PTTG and FGF-2 and its receptor FGF-R-1 in 27 differentiated thyroid cancers, and we compared this with expression in 11 normal thyroids, 25 multinodular goiters, and 13 Graves’ disease specimens. We also examined the relationship between gene expression and clinical markers of tumor behavior. PTTG and FGF-2 were overexpressed in thyroid carcinomas (9.5-fold increase, P = 0.003, and 5.0-fold increase, P < 0.001, respectively) compared with normal thyroid. Increased FGF-2 mRNA expression was independently associated with the findings of lymph node invasion (R2 = 0.71; P < 0.001) and distant metastasis (R2 = 0.55; P = 0.009) at tumor presentation, after taking into account known prognostic factors such as age and gender of the patient and size and type of the tumor. High PTTG expression was independently associated with tumor recurrence (R2 = 0.64; P = 0.003). We conclude that PTTG and FGF-2 expression are potential prognostic markers (and perhaps therapeutic targets) for differentiated thyroid cancer.
DIFFERENTIATED THYROID CANCERS (papillary and follicular carcinomas) are the most common endocrine malignancies (1). Most patients have a good prognosis but about 30% develop recurrent disease, often many years after presentation (2). There are no prospective studies of patient outcome in thyroid cancer, but it is recognized from retrospective studies that certain factors adversely affect prognosis. These include male gender, patient age more than 40 yr, tumor size at presentation greater than 1 cm, and tumor type (follicular cancers having a worse prognosis than papillary) (2, 3, 4). Distinct molecular events occurring in hyperplastic and neoplastic thyroid disease have been studied extensively. Particular attention has focused on ras mutations (5, 6) and activating TSH receptor and Gs
-subunit mutations in follicular lesions (7). Specific rearrangements of the oncogenes ret (8) and trk (9), as well as alterations in the pattern of expression of met (10), have been found in papillary carcinomas. It has been proposed that more than half of all papillary carcinomas harbor one of several chimeric oncogenes called ret/PTC (11). There are, however, no specific molecular markers of tumor behavior or prognosis described, adding to the controversy about the role of specific treatments in individual cases—for example, the need for total thyroidectomy (rather than more conservative surgery) or radioiodine ablation postoperatively (2, 3).
Pituitary tumor transforming gene (PTTG), originally isolated from GH4 rat pituitary cells, transforms cells in vitro, is tumorigenic in vivo, and induces expression of fibroblast growth factor (FGF)-2 (12, 13) and vascular endothelial growth factor (14). The human PTTG family comprises at least three homologous proteins, of which only PTTG1 (henceforth PTTG) has been studied in detail. PTTG is abundantly expressed in a variety of malignant cell lines and at low levels in normal tissues (13). Overexpression of PTTG mRNA has been reported in sporadic pituitary tumors (15) (pituitary being the first tissue from which PTTG was cloned), whereas more recently overexpression of PTTG mRNA and protein has been described in colon polyps and cancers when compared with normal colon (16). Local lymph node invasion in cases of colon cancer was associated with higher PTTG mRNA, raising the intriguing possibility of PTTG serving as a marker for prognosis.
Recently, increased expression of PTTG was demonstrated (using Northern blot analysis) in human thyroid tumors, when compared with normal thyroid (17). Interestingly, PTTG was most abundantly expressed in a subset of specimens of thyroid hyperplasia, follicular adenomas, and follicular carcinomas, with no increased expression evident in papillary cancers. Furthermore, TSH treatment of rat FRTL5 cells and primary human thyroid cells was reported to induce PTTG expression in vitro, consistent with a role for PTTG in controlling thyroid cell growth (17).
PTTG stimulates secretion of FGF-2 in vitro (13, 18), and we and others have previously described increases in FGF-2 and its receptor FGF-R-1 in both hyperplastic and neoplastic thyroid disease (19, 20, 21). Through stimulation of FGF-2 production and secretion, PTTG may enhance tumor growth and progression. Another major function of PTTG is regulating the separation of sister chromatids during mitosis. PTTG is a human securin homolog (22, 23), with a key checkpoint role in normal cell division, and is expressed in a cell cycle-dependent manner, peaking in G2/M (23, 24). Overexpression of PTTG leads to aneuploidy (24), with the resultant genetic instability likely to be an early tumorigenic event.
We set out to define the expression of PTTG and the functionally related growth factor FGF-2 and its receptor FGF-R-1 in hyperplastic and neoplastic thyroid disease. We used a highly sensitive and reproducible technique to quantify specific mRNAs and compared gene expression in hyperplastic and neoplastic thyroid disease with normal thyroids. To explore the hypothesis that expression of PTTG or FGF-2 might serve as a marker of cancer behavior, we related expression of PTTG and FGF-2 to tumor stage at presentation and to the development of recurrent disease.
Patients and Methods
Patients and thyroid tissues
Thyroid tissue was obtained at the time of surgery from a consecutive series of patients undergoing thyroidectomy for multinodular goiter (n = 25), Graves’ disease (n = 13), and thyroid cancer (n = 27; 8 follicular and 19 papillary carcinomas). Findings were compared with those from 11 samples of histologically normal thyroid tissue obtained from patients undergoing laryngectomy for laryngeal cancer; no normal thyroid specimen had any histological evidence of tumor invasion or small occult primary thyroid tumors. All of these tissues were excess to pathological requirements and were given with patient written, informed consent in accordance with local research ethics committee standards. Tissues were immediately snap frozen and stored at -80 C. Previous studies have shown material collected in this way to be suitable for mRNA and protein expression studies (14, 25).
The patients’ demographic details and thyroid function pre- and postoperatively were recorded. Pretreatment with antithyroid medication, family history of autoimmune disease, and presence of autoantibodies were documented. In cases of differentiated cancer, the tumor node metastasis (TNM) staging (2, 4) of the tumor at presentation, as well as early recurrence of the cancer during follow-up, were recorded. Recurrence was defined as evidence on imaging for recurrent disease in the thyroid bed or elsewhere or rising serum thyroglobulin in association with TSH suppression on T4 therapy. Subsequently, tumor recurrence was confirmed histologically in three of six cases, and in the remaining three by demonstrating regression of lesions on imaging and falling thyroglobulin after ablative radioiodine therapy.
RNA extraction and reverse transcription
Total RNA was extracted and reverse transcribed as described previously (14, 25, 26). Briefly, after homogenization using the Sigma Trisol kit (a single step acid guanidinium phenol-chloroform extraction procedure; Sigma-Aldrich, Dorset, UK), RNA was reverse transcribed using avian myeloblastosis virus reverse transcriptase (Promega Corp., Madison, WI) in a total reaction volume of 20 µl, with 1 µg thyroid total RNA and 30 pmol random hexamer primers.
Quantitative PCR
Expression of specific mRNAs was determined using the ABI PRISM 7700 Sequence Detection System, as described previously (14, 25, 26). Briefly, RT-PCR was carried out in 25-µl volumes on 96-well plates, in a reaction buffer containing 1x TaqMan Universal PCR Master Mix, 180 nM TaqMan probe, and 900 nM primers. All reactions were multiplexed with a pre-optimized control probe for ribosomal RNA 18S (PE Biosystems, Warrington, UK), enabling data to be expressed in relation to an internal reference, to allow for differences in reverse transcription efficiency. Primer and probe sequences were as described previously (14, 26). As per the manufacturer’s guidelines, data were expressed as Ct values (the cycle number at which logarithmic PCR plots cross a calculated threshold line) and used to determine 
Ct values and, subsequently, fold changes in gene expression. All statistics were performed with Ct values. Measurements were carried out a minimum of three times for each sample. Reactions were 50 C for 2 min, 95 C for 10 min, then 44 cycles of 95 C for 15 sec and 60 C for 1 min.
Western blots
Proteins were prepared from thyroid tissues in lysis buffer [100 mmol/liter sodium chloride, 0.1% Triton X-100, and 50 mmol/liter Tris (pH 8.3)] containing enzyme inhibitors (1 mmol/liter phenylmethylsulfonylfluoride, 0.3 µmol/liter aprotinin, and 0.4 mmol/liter leupeptin) and denatured (2 min, 100 C) in loading buffer. Protein concentration before loading was measured by the Bradford assay with BSA as standard. Western blot analyses were performed as described previously (14, 26). Briefly, soluble proteins (30 µg) were separated by electrophoresis in 12.5% sodium dodedecyl sulfate polyacrylamide gels, transferred to polyvinylidene fluoride membranes, incubated in 5% nonfat milk in PBS with 0.1% Tween, followed by incubation with antibodies to FGF-2 (1:1,000), FGF-R-1 (1:1,000), or to proliferating cell nuclear antigen (PCNA; PC10, used at 1:3,000) (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) for 16 h at 4 C. A polyclonal PTTG antibody was generated in sheep using a peptide corresponding to amino acid sequence 109–132. After purification, the antibody was validated using nonimmune sheep serum and blocking peptide and subsequently used at a 1:1,000 concentration. After washing in PBS plus 0.1% Tween, blots were incubated with appropriate secondary antibodies conjugated to horseradish peroxidase for 1 h at room temperature. After additional washes, antigen-antibody complexes were visualized by the ECL chemiluminescence detection system on Hyperfilm ECL (Amersham Biosciences, Buckinghamshire, UK). Actin expression (monoclonal anti-ß actin clone AC-15, used at 1:10,000; Sigma-Aldrich) was also determined and revealed no differences in protein loading between different groups. Protein derived from JEG-3 choriocarcinoma cells served as a positive control for PTTG and PCNA expression.
Statistical analyses
Data were analyzed using Sigma Stat software (SPSS Science Software UK Ltd., Birmingham, UK). The Mann-Whitney test was used for comparison between two groups. Correlation between pairs of mRNA results was examined using Spearman rank correlation. Multiple linear regression analysis was used to confirm independent associations with overexpression of PTTG and FGF-2, taking into account the known prognostic indicators of age, gender, size, and type of the tumor. Significance was taken as P less than 0.05.
Results
PTTG and PCNA expression
There was a 9.5-fold increase in PTTG mRNA expression (P = 0.003) in thyroid cancers (n = 27) compared with normal thyroid tissue (n = 11). There was no significant difference between papillary and follicular carcinomas (9.9-fold and 8.4-fold increase, respectively). Specimens from patients with multinodular goiters (n = 25) and Graves’ disease (n = 13) showed nonsignificantly increased levels of PTTG expression (2.4-fold, P = 0.5, and 2.1-fold, P = 0.4, respectively; Fig. 1A
). Western blot analysis (Fig. 1B) confirmed that PTTG protein expression was highest in the cancer specimens with more modest increases in hyperplastic disease states.
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). FGF-2 and FGF-R-1 expression
FGF-2 mRNA expression showed a 5.0-fold increase in thyroid cancers compared with normal thyroids (P < 0.001). Again, there was no significant difference in expression between papillary and follicular carcinomas (5.2-fold and 3.6-fold increase, respectively). A modest but significant (P = 0.02) 2-fold increase in FGF-2 expression was found in thyroid samples from patients with multinodular goiters, and a nonsignificant (P = 0.2) 1.3-fold increase was apparent in Graves’ disease (Fig. 2A). Findings from Western blot analyses of FGF-2 protein paralleled the pretranslational increases in expression of this gene (Fig. 2B).
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Associations between gene expression and clinical findings
Complete clinical details, including status during follow-up (mean duration from surgery, 31 months; range, 5–68 months), were available for 24 of the 27 cases of differentiated thyroid cancer investigated. Characteristics of the individual patients including demographic details, the TNM staging of the tumors at surgery, evidence of early recurrence, and follow-up period in months are shown in Table 1. FGF-2 mRNA was significantly higher in tumors with lymph node metastasis at presentation [no lymph nodes involved 3.0-fold increase (n = 15) compared with normal thyroid; lymph node metastases, 13.0-fold increase (n = 9) compared with normal thyroid; P < 0.001; Fig. 3A]. Similar findings were evident for tumors with distant metastases at presentation [3.9-fold (n = 19) higher expression in nonmetastasized tumors compared with 15.7-fold (n = 5) higher FGF-2 mRNA in metastasized tumors; P < 0.001; data not shown]. Multiple regression analysis confirmed independent associations of FGF-2 mRNA and lymph node involvement (R2 = 0.71; P < 0.001) as well as distant metastases (R2 = 0.55; P = 0.009), taking into account the known prognostic indicators of age and gender of the patient and size and type of tumor. FGF-2 mRNA expression was nonsignificantly higher in cancers that displayed recurrence than in those that had not recurred (6.9 vs. 4.8-fold increase; P = 0.4 compared with normal thyroid).
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). Multiple regression analysis confirmed an independent association between PTTG mRNA and early tumor recurrence (R2 = 0.64; P = 0.003). Discussion
We have demonstrated a striking increase in PTTG expression in a group of differentiated thyroid cancers compared with normal thyroid tissue, illustrating the potential importance of this gene in the pathogenesis and/or progression of thyroid tumors. We have shown a parallel increase in expression of FGF-2, which is stimulated by PTTG and which is a growth factor known to promote thyroid cell proliferation. A potentially important preliminary finding is the association between expression of FGF-2 and the TNM stage of the tumor at presentation—despite the relatively small size of our sample—and the discovery of a marked increase in PTTG mRNA in those tumors that displayed early recurrence.
High PTTG expression leads to aneuploidy (24, 27), a common feature of thyroid follicular adenomas and carcinomas as well as of many clonal human thyroid carcinoma cell lines (28, 29). In thyroid papillary cancer, aneuploidy (identified by image analysis of fine-needle aspirates) is associated with higher death rates (30). PTTG represents a potential initiator of chromosomal instability in thyroid tumors, given its role as a securin homolog (22), with PTTG overexpression leading to inappropriate cell division (23, 24).
Recently, Heaney et al. (17) described a significant (2-fold) increase in PTTG mRNA expression measured by Northern blotting in two follicular cancers, with a nonsignificant (0.84-fold) change in four of eight papillary carcinomas examined. A 1.7-fold and 1.9 fold increase was found in thyroid hyperplasia (n = 15) and follicular adenomas (n = 9), respectively. In accordance with this, our accurate quantitative RT-PCR approach confirms an approximately 2-fold increase in PTTG mRNA expression in hyperplastic thyroid conditions (n = 38) but demonstrates a markedly increased 9.5-fold induction in pretranslational PTTG expression in differentiated thyroid cancers (n = 27), with similar findings evident for both papillary and follicular carcinomas.
Uncontrolled cell proliferation is the hallmark of tumors, and most oncogenes have been shown, to date, to promote cell proliferation. Based on the findings of several studies, it has been proposed that effects of PTTG on cell proliferation are a function of the level of expression (31). Interestingly, our assessment of PCNA expression as a marker of cell turnover demonstrated no obvious differences between cancers, hyperplastic thyroid, and normal tissue. Likewise, there was no correlation between PTTG and PCNA expression, suggesting that the observed increase in PTTG expression in cancers is not simply a marker of increased cell turnover, but reflects an involvement of PTTG in some other fundamental pathway.
The intriguing idea that PTTG expression may serve as a marker of tumor behavior was first suggested in the context of pituitary adenomas in which a relationship between PTTG mRNA and invasion into the sphenoid sinus was reported in a small series (15). This was followed by description of the relationship between PTTG mRNA and protein expression and local spread of colon cancers (16). We now describe an association between early recurrence of thyroid cancer and PTTG expression in the original tumor, suggesting that PTTG promotes tumor growth, either directly or through stimulation of FGF-2. Consistent with this view is the observed relationship between FGF-2 expression and tumor staging at presentation, which supports a role for FGF-2 in mitogenesis and angiogenesis in thyroid tumors.
Despite recent advances, the preoperative diagnosis of thyroid cancer remains a challenge (32), and reliable molecular markers to aid diagnosis or treatment planning based on prognosis have yet to be found (2, 3, 4, 33). These markers could serve as an adjunct to simple clinical markers of prognosis like sex, age, and tumor size, and allow tailoring of therapy (particularly the extent of thyroid surgery and use of radioiodine ablation postoperatively) for individual patients (2, 4). Standard fine-needle aspiration biopsies are nondiagnostic in 25–40% of cases (34), one of the major diagnostic limitations being the inability to distinguish benign from malignant follicular lesions (this dilemma being relevant to about 15% of aspirates; Refs. 34 and 35). Several approaches including RT-PCR analysis for ret/PTC fusion transcripts (11) and immunohistochemical staining for galectin 3 (33, 36, 37) and CD44 (reduced levels of which may indicate unfavorable outcome; Refs. 33 and 38) have been proposed to improve the diagnostic yield of this technique. We suggest that on the basis of the present findings, studies of the role of accurate measurement of mRNAs encoding PTTG and FGF-2 in identifying malignancy in thyroid fine-needle aspirates may be warranted. In addition, further studies, based on larger numbers of excised tumors, to assess whether expression of PTTG and FGF-2 mRNAs are useful in predicting aggressive tumor behavior and, ultimately, mortality are required.
Acknowledgments
We acknowledge the financial support of the Wellcome Trust, the Medical Research Council, the British Thyroid Foundation and the Marjorie-Robinson Fund.
Footnotes
Abbreviations: FGF, Fibroblast growth factor; PCNA, proliferating cell nuclear antigen; PTTG, Pituitary tumor transforming gene; TNM, tumor node metastasis.
Received July 18, 2002.
Accepted February 18, 2003.
References
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
N G. de la Torre, I Buley, J A H Wass, and H E Turner Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour. Endocr. Relat. Cancer, September 1, 2006; 13(3): 931 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tfelt-Hansen, D. Kanuparthi, and N. Chattopadhyay The emerging role of pituitary tumor transforming gene in tumorigenesis. Clin. Med. Res., June 1, 2006; 4(2): 130 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 R. St. Bernard, L. Zheng, W. Liu, D. Winer, S. L. Asa, and S. Ezzat Fibroblast Growth Factor Receptors as Molecular Targets in Thyroid Carcinoma Endocrinology, March 1, 2005; 146(3): 1145 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ezzat, P. Huang, A. Dackiw, and S. L. Asa Dual Inhibition of RET and FGFR4 Restrains Medullary Thyroid Cancer Cell Growth Clin. Cancer Res., February 1, 2005; 11(3): 1336 - 1341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Boelaert, R Yu, L A Tannahill, A L Stratford, F L Khanim, M C Eggo, J S Moore, L S Young, N J L Gittoes, J A Franklyn, et al. PTTG's C-terminal PXXP motifs modulate critical cellular processes in vitro J. Mol. Endocrinol., December 1, 2004; 33(3): 663 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
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