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, a Growth Inhibitory Gene, in Human Pituitary Adenomas: Implications for Tumorigenesis
Neuroendocrine Unit (X.Z., H.S., D.C.D., S.R.J., Y.Z., A.K.) and Neurosurgical Service (B.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BUL 457B, Boston, Massachusetts 02114. E-mail: . aklibanski{at}partners.org
Abstract
The underlying molecular pathogenic mechanisms remain unknown in the majority of human pituitary tumors. GADD45
is a member of a growth arrest and DNA damage-inducible gene family that functions in the negative regulation of cell growth. We have found that the mRNA expression of the GADD45 gene is significantly different between normal human pituitary tissue and clinically nonfunctioning pituitary adenomas using cDNA-representational difference analysis. Although GADD45 mRNA was found in normal human pituitary tissue, it was detectable in only 1 of 18 clinically nonfunctioning pituitary tumors by RT-PCR. Furthermore, this gene was not expressed in the majority of GH- or PRL-secreting pituitary tumors (6 of 8 and 7 of 10, respectively). In colony formation assays, transfection of human GADD45 cDNA into the human pituitary tumor-derived cell line, PDFS, results in a dramatic decrease in cell growth by 88%. GADD45 also reduces colony formation in other pituitary tumor-derived cell lines, AtT20 and GH4, by approximately 60% and 50%, respectively, confirming its function in controlling cell proliferation in the pituitary. These data indicate that GADD45 is a powerful growth suppressor controlling pituitary cell proliferation, and GADD45 represents the first identified gene whose expression is lost in the majority of human pituitary tumors.
HUMAN PITUITARY ADENOMAS are the most common intracranial neoplasms, comprising approximately 10% of all diagnosed brain tumors (1, 2). The majority of human pituitary tumors are associated with hypersecretion of one or more pituitary hormones, usually of lactotroph, somatotroph, or corticotroph cell derivation, and morbidity is due to hormone excess and mass effect (3, 4). In addition, up to 40% of pituitary tumors, primarily of gonadotroph cell origin, have been classified as clinically nonfunctioning because the patients lack clinical or biochemical evidence of anterior pituitary hormone excess. Clinically, these tumors can cause considerable morbidity because of mass effect and the development of hypopituitarism (5, 6). Despite recent progresses in characterizing the pathophysiology and genetics of human pituitary tumors, the molecular mechanisms for tumor pathogenesis are still largely unclear. Investigation of commonly known oncogenes and tumor suppressor genes, such as ras, MEN-1, c-myc, Rb, p53, nm23, and gsp, has revealed that none of these genes is involved in the pathogenesis of the majority of human pituitary tumors (7, 8). Only in a significant minority of somatotroph tumors have Gs
mutations been shown to be of pathogenic significance (7, 8). The recently identified pituitary tumor-transforming gene has been shown to have increased expression in pituitary tumors (9, 10, 11), but the functions of this gene and its dysregulation in human pituitary tumors are still under investigation. Therefore, further studies to identify the molecular events responsible for the development of human pituitary tumors are critically needed.
cDNA-representational difference analysis (cDNA-RDA) is a PCR-based subtractive hybridization technique for the identification of genes that differ in their expression between two different cell sources (12, 13). It is derived from the original technique developed for use with genomic DNA to isolate the differences between two complex genomes (14). We used this technique to analyze the differences between the normal human pituitary and clinically nonfunctioning pituitary adenomas and identified several genes that are preferentially expressed in the normal pituitary, but not in tumors. An identified gene, GADD45, also known as cytokine response 6 (CR6), is a p53-regulated human gene involved in growth suppression and apoptosis (15, 16). Further studies using RT-PCR confirmed that GADD45 mRNA expression is lost in the majority of human pituitary tumors (17 of 18 nonfunctioning tumors, 6 of 8 GH-secreting tumors, and 7 of 10 PRL-secreting tumors). Transfection of a human GADD45 expression vector into the human pituitary tumor-derived cell line, PDFS, or other pituitary lines, such as AtT20 and GH4, results in a substantial inhibition of tumor cell growth. These data suggest that GADD45 may play an important role in regulating cell proliferation in the pituitary. Loss of GADD45 expression and function may be associated with uncontrolled cell growth and tumor development in the human pituitary.
Subjects and Methods
Patients
The diagnosis of pituitary tumor was established by clinical, biochemical, and radiological findings and was confirmed by immunohistochemistry after surgery. Patients with clinically nonfunctioning tumors, 12 males and 6 females, were classified based on the presence of a macroadenoma without a diagnosis of acromegaly or Cushing’s disease and with serum PRL levels of less than 100 µg/liter. The mean age of this group of patients was 59 ± 15 yr (mean ± SD). In all patients with acromegaly (mean age, 38 ± 5 yr; 4 males and 4 females), IGF-I levels were elevated and ranged from 626-2417 µg/liter, with a mean of 1395 ± 702 µg/liter. The mean age for the patients with prolactinomas was 33 ± 10 yr (5 males and 5 females). Serum PRL levels were appropriately elevated commensurate with tumor size in diagnosed prolactinomas and ranged from 35–3312 µg/liter with a mean of 519 ± 998 µg/liter. In the patients with prolactinomas or clinically nonfunctioning tumors, serum IGF-I levels were not elevated above the normal age-adjusted range. Serum -subunit concentrations were within normal limits in all patients. Immunohistochemical analysis of tumor sections revealed that all patients with prolactinomas had positive immunohistochemical staining for PRL, and all patients with acromegaly had positive staining for GH. In nonfunctioning tumors, immunocytochemical staining was negative for PRL, GH, and ACTH, but positive for -subunit, FSHß, and/or LHß. Human pituitary tumors were obtained in 0.9% saline after transsphenoidal surgery and immediately frozen in liquid nitrogen before analysis. Normal human pituitary glands were obtained 2–16 h postmortem from the Harvard Brain Tissue Resource Center (Belmont, MA). This study was approved by the Massachusetts General Hospital subcommittee for human studies.
RNA extraction and cDNA-RDA
Total RNA from pituitary tissue samples was extracted with TRIzol reagent (Life Technologies, Inc., Gaithersburg, MD). To obtain poly(A)+ RNA, total RNA from four normal human pituitary glands and four human clinically nonfunctioning pituitary tumors was pooled and purified using an Oligotex kit (QIAGEN, Valencia, CA). cDNA was prepared from poly(A)+ RNA with oligo(deoxythymidine) primers using a cDNA synthesis kit (Amersham Pharmacia Biotech, Piscataway, NJ). RDA was performed according to the protocol (12) provided by Dr. D. G. Schartz, starting with 1.5 µg cDNA. The cDNA fragments generated by three rounds of difference analysis were cloned into pBlueScript-SK and subjected to DNA sequence analysis. The DNA sequencing results were used to search GenBank to reveal the identity of each cDNA fragment.
RT-PCR
One nanogram of total RNA was used in each RT reaction with a total volume of 20 µl as described previously (17). PCR amplification was performed using PLATINUM PCR Supermix (Life Technologies, Inc.). The final volume of each reaction was 45 µl, containing 0.5 µl RT products as template DNA, 0.1 µl (10 pmol/µl) of each primer, 0.1 µl (1 µCi) [32P]dCTP, and 44.3 µl Supermix. The PCR reactions were performed with the following profiles: 94 C for 3 min, followed by 35 cycles of 94 C for 1 min, 60 C for 1 min, and 72 C for 1.5 min. After the last cycle, the elongation step was extended for 10 min at 72 C. The housekeeping gene cyclophilin A was used as an internal control as described previously (17). The mammalian expression vector pCI-neo-hGADD45 and blank vector pCI-neo (see below) were used as PCR templates for positive and negative controls, respectively. Samples from RT reactions in the absence of reverse transcriptase were also used as negative controls. The human GADD45 primers are 5'-GAAGTCCGCGGCCAGGACACAGTTCC-3' (forward) and 5'-GGTCCCCGCCGGGCTGTCACTCGG-3' (reverse). The PCR products were analyzed by PAGE in Tris/borate/EDTA buffer as described previously (17).
Cell culture and colony formation assay
Pituitary tumor-derived cell lines GH4 and AtT20 were obtained from American Type Culture Collection (Manassas, VA), cultured in DMEM with 10% FBS (Life Technologies, Inc.), and incubated at 37 C with a humidified atmosphere of 5% CO2. PDFS, a human pituitary folliculostellate cell line derived from a clinically nonfunctioning macroadenoma recently developed in our laboratory (18), and HP75, a human pituitary adenoma cell line generated by simian virus 40 large T antigen expression (19), were cultured in DMEM with 10% FBS, 0.1% insulin/transferrin/selenium, and 1% nonessential amino acids. Hemagglutinin (HA)-tagged human GADD45 cDNA (provided by Dr. H. Saito) was cloned into the mammalian expression vector pCI-neo (Promega Corp., Madison, WI) for transfection into AtT20 and GH4 or into pcDNA3.1 (Invitrogen, Carlsbad, CA), in which the neomycin-resistant gene has been replaced with a puromycin-resistant gene, for transfection into PDFS cells. For colony formation assays using PDFS cells, 1 x 106 cells were plated onto 100-mm culture dishes coated with poly-D-lysine, incubated for 24 h, and transfected with pcDNA3.1-puro-hGADD45 or blank vector pcDNA3.1-puro (2.5 µg DNA/dish) using Lipofectamine Plus reagents (Life Technologies, Inc.) according to the manufacturer’s protocol. Twenty-four hours after transfection, cells were washed with PBS, trypsinized, and plated on 100-mm tissue culture dishes in duplicates at 1:5, 1:20, and 1:50 dilutions with culture medium containing 2 µg/ml puromycin. For colony formation assays using AtT20 and GH4, cells were seeded on six-well culture plates with different concentrations of 2.0, 2.5, and 3.5 x 105 cells/well, respectively, incubated for 24 h, and transfected similarly with pCI-neo-hGADD45 or empty pCI-neo vector as a negative control (1 µg/well). The cells were then plated with 1:4, 1:8, and 1:16 dilutions in medium containing G418 (1 mg/ml). After being plated in selection medium, cells were cultured for 14 d to allow colonies to grow. The media were changed every 3 d to maintain appropriate concentrations of the antibiotics. After 14 d the cells were fixed with 1% glutaraldehyde in PBS for 10 min, washed twice with PBS, stained with 0.5% crystal violet (Sigma, St. Louis, MO) in PBS for 10 min, and washed with tap water to remove excess staining. Visibly stained cell colonies (
60 cells/colony) were counted with an electronic colony counter (Fisher Scientific, Pittsburgh, PA). Each transfection experiment was repeated at least three times to ensure consistent results. Thirty to 40 colonies from each of GADD45-transfected cell types in a duplicated experiment were picked, expanded, and stained with anti-HA antibody (Berkeley Antibody Co., Richmond, CA) as previously described (20) to detect GADD45 expression.
Results
Genes specifically expressed in normal human pituitary, but not in clinically nonfunctioning pituitary tumors, were identified using cDNA-RDA, with normal human pituitary cDNA as tester and nonfunctioning pituitary tumor cDNA as driver (12, 13). Sequence analysis revealed that of a total of 309 normal pituitary-specific cDNA fragments analyzed, 81 (26%) represented the cDNA of human GADD45 (15), also known as CR6 (16), a p53-regulated human gene. It is the most frequently identified cDNA. Table 1
represents all identified cDNA fragments and their frequencies.
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expression is lost in human clinically nonfunctioning pituitary tumors, RT-PCR was performed to analyze GADD45 mRNA in 36 human pituitary adenomas as well as in 4 normal human pituitary glands. As shown in Fig. 1, GADD45 mRNA was detected in all 4 normal human pituitary glands (Fig. 1A). However, it was detected in only 1 of 18 clinically nonfunctioning tumors (Fig. 1B), confirming our cDNA-RDA results. Furthermore, we observed that only 2 of 8 GH-secreting tumors (Fig. 1C) and 3 of 10 PRL-secreting tumors (Fig. 1D) expressed GADD45 mRNA. GADD45 mRNA was also undetectable in two human pituitary tumor-derived cell lines, PDFS (18) and HP75 (19) (Fig. 1E, lanes 2 and 3). As a control, the housekeeping gene cyclophilin A mRNA was detected in all samples (Fig. 1). Other positive and negative controls, such as pCI-neo-hGADD45, blank vector pCI-neo, and samples without RT, showed appropriate results (data not shown).
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-positive and -negative tumors with regard to patient age, gender, tumor size, or immunohistochemical or tumor hormone markers such as IGF-I or PRL. The patient with the GADD45-positive nonfunctioning tumor is a 74-yr-old man, with a recurrent macroadenoma and with immunohistochemical staining positive for -subunit but negative for all other hormones. The two acromegalic patients with GADD45-positive tumors are both women, 35 and 39 yr old, with serum IGF-I levels of 1656 and 1100 µg/liter, respectively. One tumor stained positively for GH, and the other was positive for both GH and PRL. One of the patients with a GADD45-positive PRL-secreting tumor is a 19-yr-old man with a serum PRL level of 316 µg/liter. The second is a 42-yr-old man with a serum PRL level of 642 µg/liter, who was poorly tolerant of bromocriptine treatment. The third patient with a GADD45-positive PRL-secreting tumor is a 22-yr-old woman with recurrent macroadenoma, with a serum PRL level of 36 µg/liter during bromocriptine treatment. All three tumors stained positively for PRL only.
We next tested the ability of GADD45 to inhibit the growth of pituitary tumor cells. HA-tagged human GADD45 cDNA was transfected into the human pituitary tumor-derived folliculostellate cell line PDFS. Puromycin-resistant colonies were scored after 2 wk. As shown in Fig. 2A, transfection of PDFS with a GADD45 expression vector reduced colony numbers by 88 ± 2.5% compared with blank expression vector transfection. Transfection with a control vector expressing ß-galactosidase generated similar colony numbers as the blank vector, indicating that the suppression of tumor cell growth is specifically caused by GADD45. Growth suppression by GADD45 was also observed in colony formation assays using other pituitary tumor-derived cell lines, GH4 and AtT20, by 51.3 ± 4.4% and 58.0 ± 3.1%, respectively (Fig. 2B). Among colonies formed from GADD45-transfected cells, there was no HA staining in most of the colonies and very weak staining in less than 5% of colonies (data not shown), indicating that these cells either do not express GADD45 or only express GADD45 at a very low level.
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We have found by cDNA-RDA that the human GADD45 gene is differentially expressed in normal human pituitary and human clinically nonfunctioning pituitary tumors. Furthermore, RT-PCR confirms that the GADD45 gene is not expressed in almost all clinically nonfunctioning tumors or in the majority of GH- and PRL-secreting tumors. Therefore, GADD45 represents the first human growth inhibitory gene whose expression is lost in the majority of human pituitary adenomas. Expression of human GADD45 in pituitary tumor-derived cell lines, such as PDFS, AtT20, and GH4, results in growth inhibition by more than 50%, underscoring its importance in maintaining growth control of pituitary cells.
Three similar genes, GADD45 (GADD45), GADD45ß (MyD118), and GADD45 (CR6), have been identified to belong to a family of growth arrest and DNA damage-inducible genes (15, 16, 21). The first member of this family, GADD45, was cloned from hamster cells (21). It is a p53-regulated gene (22), encoding a small acidic nuclear protein of 20 kDa. It interacts with cyclin-dependent kinase inhibitor p21WAF1/CIP1 and proliferating cell nuclear antigen (23, 24, 25, 26) and is involved in repair of DNA damage (27, 28, 29, 30). It has been shown that GADD45ß and - also interact with proliferating cell nuclear antigen, suggesting that GADD45 family members function similarly (31, 32). It has also been reported that GADD45 associates with Cdc2 kinase and disrupts the interaction between Cdc2 and cyclin B1; therefore, it may suppress cell growth by induction of G2/M arrest (33, 34, 35). Recently, Fan et al. (36) have shown that overexpression of GADD45 in HeLa and U2OS cells induces p21WAF1/CIP1 expression. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 has been well recognized to be involved in the inhibition of G1/S transition (37, 38, 39); therefore, GADD45 family members may also induce cell growth arrest by blocking G1/S transition. Furthermore, it has been reported recently that GADD45 family members are also involved in apoptosis. GADD45 expression is increased during apoptosis induced by genotoxic agents (22, 40) and by the tumor suppressor gene BRCA1 (41, 42, 43). Takekawa and Saito (15) reported that expression of GADD45, -ß, or - in ML-1 cells induces DNA fragmentation. It has been proposed that GADD45 members mediate apoptosis by activation of the MAPK and/or c-Jun N- terminal kinase signaling pathways (15, 41). Taken together these data suggest that GADD45 members inhibit cell proliferation at different levels, including G1/S and G2/M checkpoints as well as apoptosis.
cDNA-RDA employs a positive selection approach in which target cDNA fragments are sequentially enriched by favorable hybridization kinetics and subsequently amplified by PCR, whereas material common to both sources is eliminated by selective degradation. The exponential degree of enrichment of differences enables the detection of low copy number transcripts by compensating for the rarer annealing events of these species (12). This generates high sensitivity and allows the application of this technique to small amounts of starting material, such as those commonly available from the pituitary. To date, cDNA-RDA, a powerful method to investigate the difference in gene expression between two cell types, has been used widely in different applications, including the identification of transcriptional targets of hormones and transcription factors and the identification of changes in transcription associated with development, infection, and cancer (44, 45, 46, 47). Therefore, it is an ideal technique to study human pituitary tumorigenesis. Using this method, we first observed the differential expression of GADD45 between normal human pituitary and clinically nonfunctioning human pituitary adenomas. This observation was then confirmed by RT-PCR, indicating that our results are valid, and the expression of GADD45 is not only lost in most clinically nonfunctioning pituitary tumors but also in most hormone-secreting pituitary tumors. It will be interesting to determine whether several unknown cDNAs identified in our cDNA-RDA are also involved in growth control. Because the cDNA-RDA was performed between the normal pituitary gland, which contains different cell types, including corticotrophs, gonadotrophs, lactotrophs, and somatotrophs, and nonfunctioning pituitary tumors, which are primarily of gonadotroph origin, it is expected to identify proteins specific to other cell types in this process. Indeed, several such proteins, including PRL and GHRH receptor, have been identified in our cDNA-RDA, further confirming the reliability of the methodology.
It is intriguing that expression of GADD45 is lost in more than 80% of human pituitary tumors. Korabiowska et al. (48) reported a loss of GADD45 expression in 21 of 29 oral melanomas, indicating that the loss of GADD45 family members is not restricted to pituitary tumors. Our results from colony formation assays demonstrate that expression of GADD45 in the human pituitary tumor-derived cell line PDFS leads to an inhibition of tumor cell growth by 88%. The lesser degrees of growth inhibition observed in mouse AtT20 and rat GH4 cells are probably due to species differences. At this time it is not clear whether loss of GADD45 expression is a cause or a consequence of pituitary tumor formation. There is as yet no report of GADD45-null mice; however, GADD45-deficient mice have been generated and showed several of the phenotypes characteristic of p53-null mice, such as genomic instability and increased radiation carcinogenesis (49). Genomic instability in GADD45-null mice was exemplified by aneuploidy, chromosome aberrations, gene amplification, and centrosome amplification. Thymic hyperplasia was also observed in GADD45-null mice. The mouse embryo fibroblasts isolated from GADD45-/- mice exhibit increased growth and loss of normal senescence and can be easily transformed by oncogenic ras alone, whereas wild-type mouse embryo fibroblasts are not transformed under the same conditions, because primary mouse cells usually require introduction of two activated oncogenes for transformation (49). These data, combined with other previously published results and our observation of growth inhibition by GADD45, indicate a strong growth inhibitory function and an important role in maintaining genomic stability for members of the GADD45 family. Investigation of a potential chromosomal deletion or dysregulation of GADD45 gene may reveal the mechanism responsible for its loss of expression in tumors and further confirm its function in the control of normal cell growth.
In summary, we have found that GADD45 mRNA expression is lost in the majority of human pituitary tumors. Transfection of a human GADD45 expression vector into pituitary tumor-derived cells results in a substantial inhibition of tumor cell growth, consistent with its proposed role in negative regulation of cell proliferation. Therefore, GADD45 represents the first human growth inhibitory gene whose expression is lost in the majority of human pituitary tumors, and it may become an ideal target for the future development of targeted human pituitary tumor therapies.
Acknowledgments
We thank the Harvard Brain Tissue Resource Center for providing the normal human pituitary tissue, Dr. D. G. Schartz (Yale University, New Haven, CT) for providing the cDNA RDA protocol, Dr. H. Saito (Dana-Faber Cancer Institute, Boston, MA) for providing human GADD45 cDNA, and Dr. R. V. Lloyd (Mayo Clinic, Rochester, NY) for providing the HP75 cell line.
Footnotes
This work was supported in part by NIH Grant R01-DK-40947, the Jarislowsky Foundation, and USPHS Grant MH/NS 31862 (to the Harvard Brain Tissue Resource Center).
Abbreviations: CR6, Cytokine response 6; HA, hemagglutinin; RDA, representational difference analysis.
Received August 13, 2001.
Accepted December 7, 2001.
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