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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6105-6111
Copyright © 2004 by The Endocrine Society

Id1 Gene Expression Is Up-Regulated in Hyperplastic and Neoplastic Thyroid Tissue and Regulates Growth and Differentiation in Thyroid Cancer Cells

Electron Kebebew, Miao Peng, Patrick A. Treseler, Orlo H. Clark, Quan-Yang Duh, David Ginzinger and Richard Miner

San Francisco Comprehensive Cancer Center (E.K., P.A.T., O.H.C., D.G.), and Departments of Surgery (E.K., M.P., O.H.C., Q.-Y.D., R.M.) and Pathology (P.A.T.), University of California, San Francisco, California 94143-1674

Address all correspondence and requests for reprints to: Dr. Electron Kebebew, Department of Surgery, University of California/Mount Zion Medical Center, San Francisco, California 94143-1674. E-mail: kebebewe{at}surgery.ucsf.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The Id (inhibitor of DNA binding) proteins are a family of helix-loop-helix (HLH) proteins (Id1, Id2, Id3, and Id4) that lack the basic domain necessary for DNA binding. The Id1 protein enhances cell proliferation and inhibits cellular differentiation in a variety of cell types. We have previously demonstrated that the Id1 gene is up-regulated in papillary and medullary thyroid cancers. In this study we characterized the expression and distribution of the Id1 protein in normal, hyperplastic, and neoplastic human thyroid tissue. We also evaluated the effect of the Id1 gene on thyroid cancer cell growth and markers of thyroid cell differentiation. We used semiquantitative immunohistochemistry to characterize Id1 protein expression in normal, hyperplastic (multinodular goiter and Graves’ disease), and neoplastic thyroid tissue from 103 patients. Normal thyroid tissue had the lowest level of Id1 protein expression (P < 0.0001). Anaplastic thyroid cancer had the highest level (vs. benign and malignant thyroid tissues, P < 0.01). Id1 protein expression was higher in malignant thyroid tissue than in hyperplastic thyroid tissue (P < 0.02). We found no significant association between the level of Id1 protein expression and patient age, sex, tumor-node-metastasis stage, tumor size, primary tumor vs. lymph node metastasis, primary tumor vs. recurrent tumors, and extent of tumor differentiation. Inhibiting Id1 mRNA expression in thyroid cancer cell lines using Id1 antisense oligonucleotides resulted in growth inhibition (P < 0.03) and decreased thyroglobulin and sodium-iodine symporter mRNA expression (P < 0.02). In conclusion, Id1 is overexpressed in hyperplastic and neoplastic thyroid tissue and directly regulates the growth of thyroid cancer cells of follicular cell origin, but is not a marker of aggressive phenotype in differentiated thyroid cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE Id (INHIBITOR of DNA binding) proteins are a family of helix-loop-helix (HLH) proteins (Id1, Id2, Id3, and Id4) that lack the basic domain necessary for DNA binding (1, 2). Id proteins form dimers with other basic HLH transcription proteins and prevent DNA binding and gene transactivation. Id proteins, therefore, function as dominant negative regulators of ubiquitously expressed basic HLH transcription factors.

In many cell types the Id1 gene enhances cell proliferation and inhibits cellular differentiation, both in vitro and in vivo (3, 4, 5, 6, 7, 8). Cell stimulation with growth factors or activation of mitogen signal transduction pathways increases the expression of the Id1 gene (9, 10, 11, 12, 13, 14). Furthermore, in a number of in vitro models of diverse cell lineages, Id1 gene expression is down-regulated on terminal differentiation (12, 15, 16, 17, 18, 19). The Id1 gene is an important mediator of tumor cell biology, because it regulates cellular growth and differentiation as well as angiogenesis and cellular invasion (20, 21, 22, 23).

In general, Id1 gene expression is absent or low in normal adult tissue, but is elevated in a variety of benign and malignant human neoplasms (9, 10). Some investigators have shown that increased Id1 gene expression in malignant tumors is a marker of aggressive tumor phenotype, poor prognosis, and increased tumor angiogenesis (16, 21, 23, 24, 25, 26, 27, 28). We have previously demonstrated that the Id1 gene is overexpressed in papillary and medullary thyroid cancers compared with that in normal thyroid tissue from the same patients (29, 30). Little is known, however, about Id1 gene expression in normal, hyperplastic, and neoplastic thyroid tissue of follicular cell origin, and whether it is a marker of aggressive thyroid cancer. Furthermore, the effect of the Id1 gene on proliferation and differentiation of thyroid follicular cells is unknown. The primary aim of this study was to determine whether in situ Id1 gene expression was deregulated in normal, hyperplastic, and neoplastic human thyroid tissue and could therefore be a marker of thyroid cancer aggressiveness. We also modulated Id1 gene expression in thyroid cancer cell lines to directly determine its effect on growth and expression of molecular markers of differentiation in thyroid cancer cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials

The following reagents and materials were used: DMEM/Ham’s F-12 medium, L-glutamine, 1 x trypsin/EDTA solution, 1 x PBS from Cellgro Mediatech (Newark, DE); penicillin-streptomycin, fetal calf serum, and fungizone from Irvine Scientific (Santa Ana, CA); anti-Id1 rabbit polyclonal and anti-Ki67 mouse monoclonal antibodies from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); Id1 antisense and sense oligonucleotides from Genset (La Jolla, CA); Id1, ß-glucoronidase, Pendrin (PDS) and sodium-iodine symporter (NIS), thyroglobulin (Tg) primers, and probes from Applied Biosystems (Foster City, CA); TSH from Sigma-Aldrich Corp. (St. Louis, MO); streptavidin-horseradish peroxidase conjugate (Zymed Laboratories, Inc., San Francisco, CA); and LSAB+ peroxidase detection kit (DakoCytomation, Carpinteria, CA).

Thyroid tissue samples

Thyroid tissue samples, including clinical and histopathological data, were obtained for 103 patients with informed consent. The committee on human research at University of California-San Francisco approved the study. All patients with thyroid cancer were classified according to the tumor-node-metastasis staging classification. Tissue from patients with normal thyroid tissues (n = 16), multinodular goiter (n = 26), Graves’ disease (n = 9), follicular adenoma (n = 6), papillary thyroid cancer (n = 23), follicular thyroid cancer (n = 18), and anaplastic thyroid cancer (n = 5) were studied. Hematoxylin- and eosin-stained sections of each tissue studied were histologically examined to confirm the histological diagnosis.

Thyroid cancer cell lines and culture conditions

A Hürthle cell carcinoma (XTC-UC1) cell line was established and characterized in our laboratory from a patient with a breast metastasis (31, 32). Three follicular thyroid cancer (FTC) cell lines were generated from the same patient and were provided by Dr. Peter Goretzki (Dusseldorf, Germany). FTC-133 was derived from a primary thyroid tumor, FTC-236 from a lymph node metastasis, and FTC-238 from a lung metastasis. A papillary thyroid cancer cell line (TPC-1) was provided by Dr. Nabuo Satoh (Japan). The cell lines were cultured in DMEM:Ham’s F-12 supplemented with 10% fetal calf serum, penicillin (10,000 U/ml), streptomycin (10,000 U/ml), fungizone (250 mg/ml), TSH (10 mU/ml), glutamine (12.5 mg/liter), and insulin (5 mg/ml) in a standard humidified incubator at 37 C in a 5% CO2-95%O2 atmosphere. All experiments were performed with subconfluent cells in serum-free medium [DMEM:Ham’s F-12 medium with transferrin (5 µg/ml), somatostatin (10 ng/ml), glycl-L-histidyl acetate (2 ng/ml), and hydrocortisone (0.36 ng/ml)] (33).

Proliferation assay

Growth experiments were performed in 96-well plates in sextuplicate. Cells were plated in 200 µl serum-free medium. The CyQUANT cell proliferation assay was used according to the manufacturer’s instructions (Molecular Probes, Inc., Eugene, OR).

Immunohistochemistry

Archived paraffin-embedded thyroid tissues were serially sectioned (0.5 µm) and immunostained as previously described (29, 30). Polyclonal rabbit antimouse Id1 antibody was used at a 1:200 dilution. A biotinylated secondary antirabbit antibody was used at a 1:1200 dilution. The Id1 antigen-antibody complex was detected with the LSAB+ peroxidase detection kit according to the manufacturer’s instruction (DakoCytomation). The nuclei were counterstained with Gill’s hematoxylin. Immunostaining specificity was confirmed by preabsorption of the antibody with homologous and heterologous blocking peptides (Id1, Id2, and Id3). Preabsorption with only the homologous peptide abolished Id1 immunoreactivity.

The staining intensity and percentage of positive cells were scored using an ordinal scale by two independent observers blinded to the clinical and pathological data. The total score (the product of the intensity score and the proportion of positive cells score) was determined to quantify the staining as previously described (29, 30). Staining intensity was scored as: 0 = absent, 1 = faint, 2 = moderate, and 3 = strong; the percentage of positive cells was scored as: 0 = 0%, 1 = less than 33%, 2 = 33% or more but less than 66%, and 3 = 66% or more. The Spearman rank-correlation coefficient between the observers’ scoring of the immunohistochemistry slides was 0.936 (P < 0.001). Furthermore, repeated immunostaining of the same samples (n = 81) showed 100% concordance between the level of Id1 protein staining intensity and the percent positive scores.

Real-time quantitative RT-PCR

Total RNA was extracted from the cell lines using the TRIzol reagent (Invitrogen Life Technologies, Inc., Carlsbad, CA) according to the manufacturer’s instruction. Total RNA (125 ng/µl) was reverse transcribed using random hexamers with a first strand cDNA synthesis kit (Amersham Biosciences, Piscataway, NJ). Real-time quantitative PCR was used to measure Tg, NIS, and PDS mRNA expression relative to ß- glucoronidase mRNA expression as previously described (34). The PCR primers and sequences of the labeled probes are listed in Table 1Go.


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  		TABLE 1. PCR primer and probe sequences for real-time quantitative PCR

 
All PCRs were performed in a final volume of 20 µl on an ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). The PCR mixture contained 2 µl cDNA template, 4 µl 5x quantitative PCR buffer, 4.4 µl 25 mM MgCl2, 0.16 µl 25 mM deoxy (d)-NTP (dATP, dCTP, dGTP, and dUTP), 0.1 µl 1x AmpliTaq Gold, 0.2 µl forward/reverse primer (50 µM), 0.2 µl probe (20 µM), and 8.94 µl Aquanase (ribonuclease-free water). All experiments were performed in triplicate and repeated at least twice.

Statistical analysis

Data were analyzed with the StatView 5.0 (SAS Institute, Cary, NC) statistical software. A nonparametric Kruskal-Wallis test for ANOVA and a Mann-Whitney U test were used to determine differences. To determine possible correlations between immunostaining total score and other clinicopathological variables, Spearman’s correlation coefficients were calculated. P < 0.05 was considered statistically significant. Data are presented as the mean ± SD unless otherwise stated.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Id1 protein expression and localization in human thyroid tissue

A total of 103 thyroid tissues were studied, and the histopathological characteristics are summarized in Table 2Go. The level of Id1 protein expression was variable in normal, hyperplastic, and neoplastic thyroid tissues (Fig. 1AGo). Overall, normal thyroid tissue had the lowest level of Id1 protein expression (vs. hyperplastic and neoplastic thyroid tissues, P < 0.0001). Anaplastic thyroid cancer had the highest level of Id1 expression (vs. benign and malignant thyroid tissues, P < 0.01). Matched normal to neoplastic thyroid tissues from the same patient (15 follicular thyroid cancers, 22 papillary thyroid cancers, and one follicular adenoma) showed higher Id1 protein expression in the neoplastic thyroid tissues (P < 0.01). There was significantly higher Id1 protein expression in malignant thyroid tissue (papillary and follicular thyroid cancer) than in hyperplastic thyroid tissue (multinodular goiter and Graves’ disease; P < 0.02), but not when compared with benign thyroid neoplasm (follicular adenoma). Furthermore, there was no significant difference in the expression level of Id1 protein between follicular adenomas and follicular thyroid cancers, nor did the expression level differ significantly by tumor-node-metastasis stage, patient age, sex, primary tumor vs. lymph node metastasis, primary tumor vs. recurrent tumors, or degree of tumor differentiation (Table 3Go).


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  		TABLE 2. Id1 protein expression in thyroid tissue by immunohistochemistry

 


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  		FIG. 1. Id1 protein expression in normal, hyperplastic, and neoplastic thyroid tissue. A, Id1 immunohistochemistry (original magnification, x10). The arrow shows positive Id1 staining of lymphocytes in lymphoid germinal centers in a patient with multinodular goiter and thyroiditis. B, Cellular localization of Id1 proteins in the TPC-1 cell line. Coimmunostaining of Id1 protein with Ki67 (a nuclear protein) using double-fluorescent photochrome (red, Id1 protein; green, Ki67) demonstrates predominantly cytoplasmic Id1 staining.

 

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  		TABLE 3. Level of Id1 protein expression and clinicopathological factors in patients with differentiated thyroid cancer (papillary and follicular)

 
The staining distribution of the Id1 protein was heterogeneous in multinodular goiter tissues (Fig. 1AGo). The areas of higher Id1 protein expression were in nodular hyperplastic regions of multinodular tissue sections (Fig. 1AGo). The cellular localization of Id1 immunoreactivity was mostly cytoplasmic. Furthermore, coimmunostaining for the Ki67 nuclear antigen and the Id1 protein demonstrated primarily a cytoplasmic distribution of the Id1 protein (Fig. 1BGo). Most of the Id1 protein immunoreactivity was in the thyroid follicular cells, but some staining of the intrathyroidal vascular endothelium and the lymphocytes in chronic thyroiditis specimens was also observed (Fig. 1AGo).

Id1 regulates the growth and expression of markers of differentiation in thyroid cancer cell lines

Id1 mRNA levels in the FTC-236 and FTC-238 metastatic cell lines were 29.4- and 6.8-fold higher, respectively, than in the primary tumor cell line FTC-133 (P < 0.01; Fig. 2AGo). Similar to our previous finding in the TPC-1 cell line, the expression level of the Id1 gene was also down-regulated as the cells reached confluence in monolayer culture (Fig. 2BGo). This corresponds with a plateau in the growth rate of these cell lines at confluence. Inhibiting Id1 mRNA expression with Id1 antisense oligonucleotides significantly inhibited growth of the thyroid cancer cell lines compared with the effect of control treatment with Id1 sense oligonucleotides (Fig. 2CGo; P < 0.03). Inhibiting Id1 mRNA expression resulted in significant down-regulation of Tg and NIS mRNA expression, but not PDS mRNA expression (P < 0.02; Fig. 2DGo).



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  		FIG. 2. Id1 mRNA expression in thyroid cancer cell lines of follicular cell origin. A, Id1 mRNA expression in five thyroid cancer cell lines under basal culture conditions. Id1 mRNA levels in the FTC-236 and FTC-238 metastatic cell lines were 29.4- and 6.8-fold higher, respectively, than in the primary tumor cell line FTC-133. B, Id1 mRNA level and thyroid cancer cell line confluence in monolayer culture. Id1 mRNA expression decreased by 31–66% as the cells reached confluence. C, Inhibiting Id1 mRNA expression with Id1 antisense oligonucleotides (1 µM) resulted in significant growth inhibition compared with control Id1 sense oligonucleotides (1 µM) and serum-free medium without oligonucleotides in thyroid cancer cell lines at 12 h. This growth inhibition was sustained for up to 48 h (P < 0.03). D, Percent change in the levels of Id1, PDS, Tg, and NIS mRNA expression with Id1 antisense oligonucleotide (1 µM) treatment compared with control Id1 sense oligonucleotide (1 µM) in the XTC-UC1 cell line (there was a similar effect in the other thyroid cancer cell lines). Inhibiting Id1 mRNA expression with Id1 antisense oligonucleotides resulted in significant down-regulation of Tg and NIS mRNA expression at 24 h (P < 0.02), but not in PDS mRNA expression. Data are presented as the mean ± SD, except for D, in which the error bars represent the minimum and maximum percent decreases in mRNA expression.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A growing body of evidence demonstrates that the Id1 gene is a critical factor in regulating the hallmarks of human tumorigenesis; it controls cellular growth, differentiation, and invasion, as well as tumor angiogenesis in varied cell types (20, 21, 22, 23). The expression of the Id1 gene is deregulated in epithelial and endocrine cancers such as pancreatic, squamous cell, breast, endometrial, and cervical cancers (16, 25, 26, 27, 28, 29, 30, 35, 36, 37, 38, 39). To our knowledge, there has been no comprehensive study of the Id1 gene in human normal, hyperplastic, or neoplastic thyroid tissues. We found that Id1 gene expression is up-regulated in hyperplastic and neoplastic human thyroid tissue, but is not a molecular marker of an aggressive phenotype in differentiated thyroid cancer. We also found that the Id1 gene directly regulates growth in thyroid cancer cell lines of follicular cell origin and modulates the expression of the main markers of follicular thyroid cell differentiation, Tg and NIS.

Several genetic alterations and deregulated molecular factors have been observed in hyperplastic and neoplastic thyroid tissues, including activating mutations of the TSH receptor, tyrosine kinase receptors (Trk and c-Met), ras oncogene (which encodes the p21 protein), G stimulatory protein, and p53 (40). Generally, these genetic changes activate the mitogen signal transduction system of follicular thyroid cells. Because no mutations, overamplifications, or epigenetic changes in the Id1 gene have been observed, the up-regulated expression of the Id1 protein observed in hyperplastic and neoplastic thyroid tissue may represent a secondary increase in upstream signals or increased cellular proliferation (21). The up-regulated expression of the Id1 gene in hyperplastic thyroid tissue and follicular adenoma suggests that the increased level of Id1 gene expression is an early event if the Id1 gene plays a role in thyroid tumorigenesis or deregulated growth (40).

The growth regulation and differentiation of both normal and malignant thyroid cells in situ involve a complex network of external growth-modulating factors, growth factor receptors, signal transduction systems, and cellular genetic elements (41, 42, 43, 44). Although increased Id1 protein expression in some human epithelial cancers has been associated with an aggressive cancer phenotype, we did not find any significant relationship between the level of Id1 protein expression and an aggressive phenotype in differentiated thyroid cancer. This may be because the behavior of differentiated thyroid cancers is heterogeneous, because of the semiquantitative nature of the immunohistochemistry technique, or because the number of samples studied was insufficient to detect a small difference. Nonetheless, Id1 protein expression was significantly higher in anaplastic thyroid tissue, which is the most aggressive form of thyroid cancer. Therefore, the level of Id1 protein expression may be a marker of only very aggressive thyroid cancers.

As has been observed in other cell systems, Id1 gene expression decreased with decreased thyroid cancer cell growth. Directly inhibiting Id1 gene expression resulted in growth inhibition of all thyroid cancer cell lines studied. This finding in addition to up-regulated expression of the Id1 protein in hyperplastic and neoplastic thyroid tissue suggest that the Id1 gene is an important regulator of follicular thyroid cell growth. The Id1 gene might regulate thyroid cancer cell proliferation through its known effect on cyclin-dependent kinase inhibitors, such as p16, p21, and p27 (39, 45, 46). Consequently, drugs that inhibit Id1 gene expression may be good candidates for treating patients whose aggressive thyroid cancer does not respond to conventional treatment approaches (47, 48).

In contrast to other positive regulators of cellular proliferation, the Id1 gene also functions as an inhibitor of differentiation in some in vitro and in vivo models of differentiation (11, 17, 18, 24, 48, 49). We found that inhibiting Id1 mRNA expression, however, down-regulated Tg and NIS expression. Thyroid cancers of follicular cell origin are unique in that the differentiation markers, Tg and NIS, may be expressed at similar levels as in normal, hyperplastic, and benign neoplasms (50, 51). They are usually down-regulated in poorly differentiated thyroid cancers of follicular cell origin. The opposite effect of the Id1 gene on the expression of markers of follicular cell origin may reflect more global cellular phenomena of arrested cell cycle progression and gene expression associated with inhibiting Id1 gene expression (25). Furthermore, the effect of the Id1 gene on cellular differentiation may be diverse and dependent on the cell system analyzed.

In summary, the Id1 gene is overexpressed in hyperplastic and neoplastic thyroid tissue and directly regulates the growth of thyroid cancer cells of follicular cell origin, but it is not a marker of an aggressive phenotype in differentiated thyroid cancer. Agents that inhibit expression of the Id1 gene would be good candidate drugs for treatment of patients with advanced thyroid cancer.


   Footnotes
 
This work was supported in part by the Robert Wood Johnson Foundation/Harold Amos Medical Faculty Development Program, Hellman Family Grant, and the University of California Cancer Research Coordinating Committee.

Abbreviations: d, Deoxy; FTC, follicular thyroid cancer; HLH, helix-loop-helix; Id, inhibitor of DNA binding; NIS, sodium-iodine symporter; PDS, Pendrin; Tg, thyroglobulin.

Received June 28, 2004.

Accepted September 9, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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