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Differential expression of kinase genes in primary hyperparathyroidism: adenoma versus normal and hyperplastic parathyroid tissue.

* Context.--Differentiation between adenoma and hyperplasia or even normal parathyroid tissue is difficult and based mainly on the surgeon's skill. Exploration of genes that express differentially in these various tissues using microarrays and other sophisticated research tools will enable identification and perhaps development of new methods of perioperative diagnosis.

Objective.--To assemble a panel of kinase genes to differentiate parathyroid adenoma from normal and hyperplastic parathyroid tissue.

Design.--RNA was extracted from adenoma, hyperplasia, and normal parathyroid tissue and hybridized to a microarray containing 359 human cDNAs of known kinase genes. Signals of exposure were scanned and quantified with software for digital image analysis. Semiquantitative reverse transcriptase polymerase chain reaction analysis of sample genes was performed, up-regulated or down-regulated, to validate the microarray results.

Results.--The ratio values considered significant (<0.5 or >1.5) suggest that genes up-regulated in parathyroid adenoma are those responsible for blood vessel angiogenesis and genes belonging to the cyclin-dependent kinase inhibitor groups. Genes down-regulated in parathyroid adenoma are related to cellular growth and apoptosis--genes from the mitogen-activated protein kinase group and DNA-dependent protein kinase group. An interesting gene downregulated in the parathyroid adenoma samples is related to the serine/threonine protein kinases that exert a key function in calcium handling. A panel of 5 genes was defined: p19, p21 and the gene for vascular endothelial growth factor from the up-regulated group, and the gene for protein kinase C and SGK from the down-regulated group. Reverse transcriptase polymerase chain reaction confirmed the microarray results for these genes.

Conclusions.--The kinase genes panel presented can be used to differentiate parathyroid adenoma from normal and hyperplastic parathyroid tissue in particular when histopathology fails to provide a decisive diagnosis.


Primary hyperparathyroidism is characterized by hypersecretion of parathyroid hormone in spite of hypercalcemia. Primary hyperparathyroidism is caused by a single gland adenoma in most patients (up to 90%) or multiglandular hyperplasia (10%-15%). Since the management of primary hyperparathyroidism is accomplished via surgical procedure, it is important to know whether a single adenoma is present or the condition is caused by hyperplasia of all parathyroid glands. Thus, with the advent of advanced localizing studies a focused, minimally invasive parathyroidectomy would seem the procedure of choice. However, preoperative studies do not differentiate adenoma from hyperplasia of all parathyroid glands. Thus, the surgical decision-making is still based on the surgeon's experience. Even histopathologic differentiation between adenoma and hyperplastic parathyroid tissue is difficult because there are no specific abnormalities that distinguish between the 2 entities. (1) Adenomas are considered neoplasms, while hyperplasia is a nonneoplastic condition. Clonal studies have suggested that hyperplastic parathyroids initially grow polyclonally and then foci of chief hyperplasia undergo somatic mutations and transform into monoclonal neoplasia-adenomas. (2,3) The most common deranged genes are the multiple endocrine neoplasia type 1 tumor suppressor gene, which is inactivated in 20% of adenomas, (4-6) and the oncogene cyclin D1, which is overexpressed in at least 20% of adenomas. The result of overexpressed genes in adenomas versus normal parathyroid identifies several putative oncogenes implicated in cell growth and transcriptional regulation, such as the cyclin D1 gene. Cyclin D1 overexpression is in agreement with the protein overexpression previously detected by immunohistochemistry in parathyroid adenomas. (7,8) A pericentric inversion with breakpoints at 11q13 and 11p15 is suggested to bring the cyclin D1 oncogene under the influence of the 50 regulatory sequences of the parathyroid hormone gene, which results in dramatic overexpression of cyclin D1. Although this rearrangement has been described in a few tumors only, cyclin D1 protein overexpression has been reported in 18% to 40% of adenomas by immunohistochemistry studies. (4,7-12) Cyclin D1 promotes the G1-S-phase transition, probably by activating a cyclin-dependent kinase, but may also interact with other proteins and influence other pathways related to cell proliferation. Telomerase and RET gene mutations were found not contributory. (13,14) Tumors of primary hyperparathyroidism also frequently demonstrate loss of heterozygosity on chromosomes 1p, 6q, 9p, 11p, 11q, and 15q, (15) and gains on chromosomes 16p and 19p, as determined by comparative genomic hybridization. (16,17) The eukaryotic cell cycle is driven forward by cyclins, which form holoenzymes together with their cyclin-dependent kinase (CDK) partners. (18-20) Cyclin-dependent kinase inhibitors (CKIs), which generally inhibit cell cycle progression, (18) modulate the activity of the holoenzymes. In humans there are 2 families of CKIs, the kinase inhibitor proteins and the inhibitors of cdk4 (INK4). (21) The kinase inhibitor protein group includes p21/WAF1/CIP1, p27/Kip1, and p57/ Kip2, which are homologous in the amino terminus and have a broad specificity for CDKs. The INK4 group consists of p15, p16, p18, and p19 and has a more restricted CDK specificity. During tumorigenesis, normal cell cycle regulation is lost and restriction point abnormalities such as overexpression of cyclins and loss of function of CKIs become common features. Recently, it was shown that the kinase inhibitor protein and INK4 group changes contribute to the understanding of hyperparathyroidism and even can be used to distinguish the histopathological entities of adenoma and hyperplasia. (22-25) In order to evaluate the impact of other CKIs as well as the expression of additional additional kinase genes that may differ among adenoma, hyperplasia, and normal parathyroid tissue, we explored kinase gene expression with kinase-specific microarray and semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis.


Tissue Samples

Tissue samples from patients with sporadic, nonfamilial primary hyperparathyroidism were obtained at surgery. Normal parathyroid tissue was available only when parathyroid glands were devascularized during procedures for thyroid tumors. Part of the tissue was submitted to histopathologic examination. The second part was dissected free of any connective tissue and sliced into small pieces of 1 x 1 x 1 mm that were snap-frozen in liquid nitrogen and stored at -80[degrees]C until use. All tissue sample collection was performed with pathologist supervision and confirmed by histopathologic examination in accord with the ethical standards of the Committee on Human Experimentation of our institution.

RNA Preparation and Hybridization

Tissue samples were treated with STAT-60 (Tel-Test Inc, Friendswood, Tex) and homogenized by Polytron PT2100 (Kinematica AG, Lucerne, Switzerland). Total cellular RNA was extracted by following the instructions of the manufacturer; samples were treated with DNase I (Clontech Laboratories, Inc, Palo Alto, Calif) at 37[degrees]C for 30 minutes and reextracted with phenol according to standard procedure.

The Custom Atlas Array

The Custom Atlas Array (Clontech) includes 359 human cDNAs of known kinase genes, divided into categories. In addition, the array includes 9 housekeeping genes for internal control of gene expression, genomic DNA spots as orientation markers and controls of labeling efficiency, and negative controls immobilized in duplicate dots on a nylon membrane.

RNA Labeling and Hybridization

The kit contains all necessary ingredients for RNA labeling, probe purification, and hybridization. Five micrograms of total DNA-free RNA from each tissue sample were labeled by [alpha]-[[sup.32]P] dATP. The cDNA probe was purified on a special (included) column. Equal amounts of labeled probe (about [10.sup.7] cpm) prepared from adenoma and hyperplastic tissue were hybridized to the array. Following several washings the arrays were exposed to x-ray films at -80[degrees]C for 7, 10, and 16 hours. The entire procedure was repeated twice to ensure adequate results.

RNA Identification and Comparison

Atlas Image 2.0 by Clontech software was used for microarray experimental data analysis. Signals of exposure were scanned and quantified with Atlas Image for digital image analysis. This program is designed to compare gene expression profiles and generate a detailed report. Briefly, after reading intensities of the spots and the alignment of the arrays to the grid template the background calculation is performed. The program generates intensity values (the average of the total signal from the left and right spots in double-spotted arrays). When using the average multiple arrays function, the adjusted intensities on each array are normalized and then the data are averaged to create the composite array. A different normalization coefficient is calculated for each array independently and applied to all genes on the corresponding array. The adjusted intensity for a gene is the intensity value minus the background value multiplied by the normalization coefficient. The ratio value is calculated for each gene compared to "household genes" of each array, and the results are compared on a regular Microsoft Excel (Microsoft Corp, Redmond, Wash) spreadsheet. A ratio value greater than 1.5 or less than 0.5 is considered a significant change.

Comprehensive information on the genes included in the array is found at Clontech's AtlasInfo Bioinformatics Database (atlasinfo.

Semiquantitative RT-PCR Analysis

Analysis of sample genes by RT-PCR was performed to validate the microarray results.

For the RT-PCR reaction, synthesis of cDNA was performed using p(dT) 15 primer (Boehringer, Mannheim, Germany) to initiate reverse transcription of 5 [micro]g total RNA with 400 units of Reverse Transcriptase (Gibco BRL, Gaithersburg, Md). Two microliters of the cDNA was used as a template for the PCR reaction with Taq polymerase (Takara, Otsu, Japan). The sequences of the oligonucleotide primers were: for p19 INK4: forward 5'-GAGGAGCACAGTTTGTGGCTTATAGGTG-3', and reverse 5'-CTTAAATGCTCTGCCCTTGGGTCTCGT-3'; for p21 AK-2: upstream 5'-CAGAACAGTGGGCTCGATTACTACAG-3', downstream 5'-CATGTGAATCACCAACTGGTGCAGG-3'; for SGRK upstream 5'-CTGCATTCACTGAACATCGTTTATAGAG-3', downstream 5'-CCATACAGCATCTCATACAAGACAGC-3'; for PCKalpha 5'-CCGGCCAGTGGATGGTACAAGTTGC-3' upstream, and 5'-CTCCACGTCATCATCCTGAATCACCACA-3' downstream; for VEGFR3 upstream 5'-CAGGTGCTTCCCAGACACTGGCGT TACT-3', and downstream 5'-ACTCATATTACCAAGGAATA ACTGGCGGGCA-3'. The PCR reaction was performed in a 25- [micro]L volume in the presence of 5% dimethyl sulfoxide for 28 cycles (94[degrees]C for 5 min, 94[degrees]C for 30 s, 57[degrees]C for 30 s, and 72[degrees]C for 30 s) for p19 INK4, p21 AK-2, and for SGRK and with a temperature of 62[degrees]C for PKC alpha and VEGFR3. The number of cycles in all PCR assays was calibrated to ensure that PCR amplification was carried out in the linear phase. The integrity of cDNAs was assayed by PCR analysis with ubiquitous cell cycle-independent histone variant H3.3. The product was separated by electrophoresis in a 2.5% agarose gel and detected with ethidium bromide dye. The products were quantified using molecular analysis software (Image Pro-Plus version 3.0, Media Cybernetics, Silver Spring, Md).


Histopathologic examination confirmed the diagnosis of chief cell hyperplasia of all 3 1/2 glands (1 patient), parathyroid adenoma (3 patients), and normal parathyroid tissue (2 patients). The patients' calcium levels returned to normal following surgery (removal of the adenoma or 3 1/2 parathyroid glands for hyperplasia). The numerical results of the array comparison were processed as a spreadsheet-like tabular format for further analysis.

Significantly up-regulated or down-regulated genes expressed in the parathyroid adenoma array are represented by the ratio values. Ratio values less than 0.5 or greater than 1.5 were considered statistically significant. The group of genes up-regulated in parathyroid adenoma is described in Table 1. Significantly up-regulated kinase genes in the adenoma specimens belong to the cell cycle regulators group (CDKs) or the angiogenesis group (VEGF), and include a few genes related to intracellular transducers, effectors, and modulators (IP3).

Kinase genes down-regulated in parathyroid adenoma are listed in Table 2. Significantly down-regulated kinase genes of the adenoma specimens belong to the apoptosis group (MAPK, DNA-PK) and serine/threonine kinases group (PKC, SGK, NIMA).

Semiquantitative RT-PCR results (Figure) revealed similar values to the ratio values generated by the microarray. Up-regulated genes: CDK family (p19) microarray ratio value 1.6, RT-PCR result 1.74; CDK inhibitors (p21) microarray ratio value 2.07, RT-PCR result 2.05; angiogenesis gene FTL4 (VEGF) microarray ratio value 3.4, RT-PCR result 3.2. Down-regulated genes belong to the serine/threonine kinases group PKC microarray ratio value 0.559, RTPCR result 0.376. The SGK gene RT-PCR result varied: 1.2 compared to microarray ratio value 0.4 due to a technical problem with the normal sample of the RT-PCR.



A reliable method of differentiation among adenoma, hyperplasia, and normal parathyroid tissue will greatly facilitate management of patients with primary hyperparathyroidism. Preoperative studies, the extent of surgery, and even follow-up examinations can alter patient management accordingly, reducing costs and simplifying the management process.

Previous immunohistochemical studies have shown a decrease in p27-positive cells in both adenoma and hyperplastic parathyroid glands compared to normal glands, (22,23) yet hyperplastic glands had a threefold higher number of p27-positive cells compared to adenoma. Other studies show a decrease in p27 mRNA expression in parathyroid adenomas, and a loss of p18 and p21 in 42% of adenomas evaluated. (25) Our results, although in only 3 adenoma patients, revealed significant up-regulation of expression of kinase genes from both CKI groups. Overexpression of cyclin-dependent kinase inhibitor 1 (WAF1) from the kinase inhibitor protein group and PAK-[gamma] (p21- activated kinase [gamma]), combined with overexpression of CDKN2D (p19-INK4D) and cell division protein kinase 3 (CDK3), denote a major derangement in the regulation of cell-cycle progression. This aberrant expression has been associated with both benign and malignant tumors. (26) Franklin et al (24) reported increased CDK activity in the G1 phase of p18-depleted and p27-depleted mice, which develop parathyroid tumors and hyperplasia. Altered CKI expression and overexpression of CDKs may promote cell cycle progression, explaining the change from hyperplasia to adenoma. Moreover, up-regulated genes that increase angiogenesis and production of blood vessels were reported in our previous work. (27) Overexpression of vascular endothelial growth factor receptor 3 (VEGFR3 or FLT4) denotes derangement in a key regulator of blood vessel angiogenesis in adult tissues. Kaipainen et al (28) showed increased expression of FLT4 in lymphatic sinuses in metastatic lymph nodes and in lymphangioma, concluding that FLT4 is a marker for lymphatic vessels and endothelial venules in human adult tissues.

Significantly down-regulated genes in our study included the MAPK group and DNA-dependent protein kinase group, which are kinases involved in cellular growth and apoptosis. Mitogen-activated protein kinases are also involved in IGF1 receptor activation, another major survival factor that protects cells from apoptosis. (29) Additional kinase genes involved in cell-cycle regulation that were down-regulated in our samples belong to the serine/threonine protein-kinase group (PKC-[alpha], SGK, NIMA-related protein kinase 2 and 3). (30) Similar results were noted by Velazquez-Fernandez et al. (31) Recently, PKC-[alpha] was attributed a key function in regulation of cardiac contractility and ionized calcium handling in myocytes. (32)

Expression of cell-cycle regulatory proteins has been researched in parathyroid tumors; however, since parathyroid neoplasms may contain multiple molecular changes, one should investigate various genes in the same tissue, as shown by Stojadinovic et al (33) in their detailed study of the components of the p53 pathway. Recently, Velazquez- Fernandez et al (31) showed in their comprehensive work that powerful microarray technology can define genes to differentiate between these pathologic entities.

Our results define kinase genes--either down-regulated or up-regulated--that differ significantly and can be used as good markers for differentiating parathyroid adenoma from normal or hyperplastic parathyroids. These genes belong to the CKI groups, although changes in CKI groups reported by others are not coincident with our results. (25) Rosen et al (34) compared parathyroid adenomas with normal parathyroid tissue and described among the significantly changed genes 7 calcium-ion binding signaling proteins. In our opinion, attention should be directed to expression of functional genes that influence calcium metabolism, like PKC-[alpha], since no evidence has been shown as to the genetic change in the set point of parathyroid cells of adenoma or hyperplasia. Moreover, it is our inclination to recommend inclusion of significantly up-regulated and down-regulated genes in a panel of genes that can better differentiate between the 2 specific physiologic conditions in particular when histopathology fails to retrieve a conclusive result.

Accepted for publication July 7, 2006.


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Pinhas P. Schachter, MD; Suhail Ayesh, PhD; Imad Matouk, BSc; Tamar Schneider; Abraham Czerniak, MD; Abraham Hochberg, PhD

From the Department of Surgery A, E.Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv (Drs Schachter and Czerniak); and the Department of Biological Chemistry, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (Drs Ayesh and Hochberg, Mr Matouk, and Mrs Schneider).

The authors have no relevant financial interest in the products or companies described in the article.

Reprints: Pinhas P. Schachter, MD, Department of Surgery A, E.Wolfson Medical Center, Holon 58100, Israel (e-mail:
Table 1. Adenoma: Up-Regulated Genes

Gene Normalized GenBank
Code Ratio Value Code Description

A1C 1.9595822 D17517 Tyrosine-protein kinase
 receptor tyro3 precursor; rse; sky;

A1J 3.401016 X68203; Vascular endothelial growth
 X69878; factor receptor 3 precursor
 U43143 (VEGFR3); FMS-related tyrosine
 kinase 4 (FLT4)

A1M 1.606302 AB005060 NTAK protein (neural- and thy-
 mus-derived activator for
 ERBB kinases)

A2H 1.61554456 U40343; Cyclin-dependent kinase 4
 U20498 inhibitor 2D (CDKN2D); p19-

A4N 1.5439281 M84443 Galactokinase 2

B5D 2.073659 U24153 p21-activated kinase [gamma] (PAK-
 [gamma]; PAK2); PAK65; S6/H4 kinase

B5G 1.678762 X66357 Cell division protein kinase 3

B7H 1.8243904 L38734 Ephrin-B2 precursor; EPH-related
 receptor tyrosine kinase
 ligand 5 (LERK-5); HTK
 ligand (HTK-L)

C2H 1.7156008 U78576 68-kD type I phosphatidylinosi-
 tol-4-phosphate 5-kinase [alpha]
 (PTDINS[4]P-5-kinase); 1-
 kinase; diphosphoinositide

C3B 1.7593834 X97630 Serine/threonine protein kinase

C5N 1.5845486 X57206 1D-myo-inositol-triphosphate
 3-kinase B; inositol 1,4,5-tri-
 phosphate 3-kinase (IP3 3-kinase;

C7A 1.6178393 X85106 Ribosomal protein S6 kinase II
 [alpha] 2 (S6KII-[alpha] 2); ribosomal
 S6 kinase 3 (RSK3)

D3A 1.7254565 J02853 Casein kinase II [alpha] subunit

D4E 1.6851304 N23941 Cyclin-dependent kinase
 inhibitor 1

D5F 1.6019734 AF074382 I-[kappa]-B kinase [gamma] subunit
 (IKK [gamma])

D7C 1.6257932 X80693 Casein kinase I [alpha] isoform
 (CKI-[alpha]); CK1; CSNK1A

Table 2. Adenoma: Down-Regulated Genes

Gene Normalized GenBank
Code Ratio Value Code Description

A1H 0.6273743 U35835; DNA-dependent protein kinase
 U47077 (DNA-PK); DNA-PK catalytic
 subunit (DNA-PKCS)

A7D 0.55890095 M22199 Protein kinase C [alpha] polypeptide
 (PKC-[alpha]; PKCA)

B1A 0.53279674 AF064771 Diacylglycerol kinase [alpha]

B1G 0.65312135 L11285 Mitogen-activated protein
 kinase kinase 2 (MAP kinase
 kinase 2; MAPKK2; MAP2K2;
 PRKMK2); MAPK/ERK kinase
 2 (MEK2)

B2A 0.18462232 AF067518 PITSLRE protein kinase [beta] SV7

B2B 0.56211936 X94453 [delta] 1-pyrroline-5-carboxylate
 synthetase (P5CS) [includes
 glutamate 5-kinase ([gamma]-glutamyl
 kinase) (GK); [gamma]-glutamyl
 phosphate reductase (GPR)
 semialdehyde dehydr

B4J 0.5244766 AB004884 PKU-[alpha]

B5F 0.5446254 U78876 MAPK/ERK kinase kinase 3
 (MEK kinase 3; MEKK3)

B5M 0.46771598 U11050 Serine/threonine-protein kinase
 NEK2; NIMA-related protein
 kinase 2; NIMA-like protein
 kinase 1; HSPK 21

C1A 0.27563244 U51004 Hint protein; protein kinase C
 inhibitor 1 (PKCI1)

C2C 0.65812165 Z29067 Serine/threonine-protein kinase
 NEK3; NIMA-related protein
 kinase 3; HSPK 36

C4D 0.4384285 AJ000512 Serum- and glucocorticoid-regulated
 protein kinase (SGK)

C6E 0.60825884 U77352 MAP kinase-activating death
 domain protein

C7I 0.61404467 Y12856 Catalytic AMP-activated protein
 kinase [alpha] 1 (PRKAA1;

D1D 0.44959486 Z15108 Protein kinase C [zeta] type

D2G 0.27655166 V00572 Phosphoglyceride kinase 1
 (PGK1; PGKA); primer
 recognition protein 2 (PRP2)

D2H 0.34420875 X80692 Mitogen-activated protein
 kinase 6 (MAP kinase 6;
 MAPK6; PRKM6); p97-MAPK;
 extracellular signal-regulated
 kinase 3 (ERK3)

D5C 0.5221379 X57346 14-3-3 protein [beta]/[alpha]; protein
 kinase C inhibitor protein-1
 (KCIP-1); protein 1054
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Author:Schachter, Pinhas P.; Ayesh, Suhail; Matouk, Imad; Schneider, Tamar; Czerniak, Abraham; Hochberg, Ab
Publication:Archives of Pathology & Laboratory Medicine
Date:Jan 1, 2007
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