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Tumor Biology |
Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, 20123 Milan, Italy [P. F., D. G., O. R., E. V., L. L.]; Dipartimento di Biologia e Patologia Cellulare e Molecolare, c/o Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy [G. M. P., M. F., A. F.]; Department of Neurosurgery, Ospedale San Raffaele, 20132 Milan, Italy (M. L., P. M.); Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [C. M. C.]; Department of Biology Genetics, University of Milan, 20133 Milan, Italy [L. L.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Pituitary tumorigenesis is generally considered a model of the multistep process of carcinogenesis, in which molecular genetic alterations represent the initializing event that transforms cells, and hormones and/or growth factors play a role in promoting cell proliferation. Somatic mutations identified in other malignancies are usually absent from pituitary tumor samples, and the molecular events leading to pituitary tumorigenesis remain unknown. Only a small fraction of pituitary adenomas have activating mutations of G-protein subunit 
(7)
. Moreover, MEN1A mutations, constantly found in patients affected by the MEN-1 syndrome, which includes pituitary adenomas, have never been found in sporadic pituitary adenomas (8)
. Equally, although p27kip1 and Rb inactivation is associated with the development of pituitary adenomas of the intermediate lobe in mice, no such mutations have been identified in human pituitary adenomas (9)
. Only recently, a powerful transforming gene, PTTG, has been implicated in pituitary tumorigenesis (10)
. In fact, PTTG, isolated from rat growth hormone-secreting pituitary tumors, is expressed in functional human adenomas but not in normal pituitary tissue and exerts striking transforming effects in vitro and in vivo.
Very recently, a valuable hint for HMGA2 as a candidate gene in pituitary oncogenesis came from the phenotype of mice generated in our laboratory. HMGA2 is a member of the HMGA family that includes HMGA1, which encodes the HMGA1a and HMGA1b proteins through an alternative splicing mechanism (11) . HMGA proteins are involved in the regulation of chromatin structure, and HMGA DNA-binding sites have been identified in the functional regions of many gene promoters (12 , 13) . HMGA2 plays a critical role in determining body size and adipocytic cell differentiation (14 , 15) . In fact, disruption of this gene results in a pygmy phenotype and a prodigious reduction in fat tissue (14) . Conversely, overexpression of an activated form of HMGA2 induces a giant phenotype associated with abdominal/pelvic lipomatosis (16) .
The HMGA genes are abundantly expressed during embryogenesis (14 , 17) , but not in normal adult tissues. However, they are frequently overexpressed in several human neoplasias including thyroid (18 , 19) , prostate (20) , cervix (21) , colorectum (22 , 23 , 24) , and pancreas carcinomas (25) , and seem to play a critical role in cell transformation. Indeed, the block of HMGA2 protein synthesis prevents rat thyroid cell transformation by murine transforming retroviruses (26) , and an adenovirus carrying the HMGA1 gene in antisense orientation induces cell death of thyroid, breast, and lung carcinoma cell lines (27) .
In an attempt to understand the role of HMGA2 rearrangements and overexpression in human benign tumors, we generated transgenic mice carrying a wild-type or a truncated HMGA2 (deprived of the acidic COOH-terminal tail) construct under the transcriptional control of the cytomegalovirus promoter (16) . Most (85%) female transgenic mice (carrying either the wild-type or the truncated HMGA2 construct) develop pituitary adenomas that secrete prolactin and growth hormone by the age of 6 months. The transgenic males develop the same phenotype but with a lower penetrance (40%) and a longer latency period (about 18 months).4 On the basis of the mouse system, we postulated that HMGA2 overexpression may be a factor involved in human pituitary adenomas. Indeed, trisomy of chromosome 12, which harbors HMGA2, represents the most frequent cytogenetic alteration in human prolactin-secreting pituitary adenomas (28 , 29) , and structural rearrangements on chromosome 12 are recurrent in prolactinomas (29) .
Using FISH analysis and BAC probes, which encompass the entire HMGA2 locus, we demonstrated amplification of HMGA2 in most of human prolactinomas. Consistently, an induction of HMGA2 protein expression was detected. These results strongly suggest a critical role of HMGA2 overexpression in human prolactinomas.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. PA 83, 85, and 88 are invasive macroprolactinomas that did not respond to dopaminergic treatment. Cases PA 78, 87, and 94 were three microprolactinomas that, after an initial response to drugs, showed a progressive rise of prolactin levels and, in the case of PA 94, also a slight increase in tumor size. Prolactin levels decreased in PA 89 without any tumor shrinkage. The patient, a young girl, had previously received surgery for primary hyperparathyroidism, thus raising the suspicion of a multiple endocrine neoplasia 1 syndrome not confirmed by MEN1 mutations analysis. The PA 90 diagnosis came about because of hemorrhage in a previously undetected and untreated macroprolactinoma.
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Cell Cultures and Cytogenetic Analysis.
The primary pituitary cell cultures (24–48-h incubation and 7–10-day short-term propagation) were set up as described elsewhere (14)
. The phytohemagglutinin-stimulated peripheral blood cultures were set up according to standard procedure. The QFQ banding technique was used for cytogenetic analysis, and the International System for Human Cytogenetic Nomenclature was adopted (30)
.
Probes for FISH Analysis.
We used two partially overlapping PAC clones that targeted the third intron and the 3' portions of the HMGA2 gene (clone 12/1, spanning 35 kb of 3' intron 3 and the 3' portions of the gene, and clone 20422, encompassing the entire intron 3 region), and two overlapping BAC clones (698 i6 and 669 g18) that encompassed the 5' (5' untranslated region, exon 1, exon 2, and exon 3) and the 3' (exon 3, exon 4, exon 5, and 3' untranslated region) portions of the gene. BAC clones were from library RPCI 11 (31)
, clone 698 i6 and clone 669 g18 were from library plate 697–704 and 665–672, respectively. PAC clones were provided by J. Bullerdiek (University of Bremen, Bremen, Germany) (32)
. FISH analysis confirmed that all of the PACs and BACs mapped to 12q14–15. We also used the pBR12 alphoid-specific probe of chromosome 12 (D12Z3; Ref. 33
). Additional commercial chromosome-specific and painting probes (Oncor) were used when necessary for metaphase FISH.
FISH Studies.
The procedure described by Lichter et al., 1990 and Lichter and Cremer, 1992 (34
, 35)
, with minor changes, was used for dual-color FISH experiments on interphase nuclei and metaphases from direct tumor or short-term culture preparations. Wherever possible QFQ-banded metaphases were used for FISH experiments after slides were washed several times in fixing solution. Briefly, the probes were labeled by nick translation with biotin or digoxygenin (Roche Molecular Biochemicals, Basel, Switzerland). For each in situ hybridization experiment, 200 ng of labeled alphoid probe and/or 500 ng of labeled BAC/PAC probes were used in a 10-µl volume of hybridization solution. The FISH procedure, detection of biotin- and digoxygenin-labeled probes, nuclei/chromosome counterstaining, and digital image analysis are described elsewhere (29)
. The images were edited using Adobe Photoshop, Version 5.5 (Adobe System, Mountain View, CA).
RNA Extraction and Reverse Transcription-PCR Analysis.
Pituitary adenomas were rapidly dissected, frozen on dry ice and stored at -80°C. Total RNA was extracted using TRI-reagent solution (Molecular Research Center, Cincinnati, OH) according to the manufacturer’s protocol. Five µm of total RNA, digested with RNase-free DNase, were reverse-transcribed using random hexanucleotides as primers (100 mM) and 12 units of avian moloney virus reverse transcriptase (Promega). The cDNA was amplified in a 25-µl reaction mixture containing 0.2 mM dNTP, 1.5 mM MgCl2, 0.4 mM each primer, and 1 unit of Taq DNA polymerase (Perkin-Elmer). After a denaturing step (95°C for 2 min), the cDNA was further amplified in 20 PCR cycles (95°C for 1 min, 58°C for 30 s, and 72°C for 30 s). The following primers were used to amplify the HMGA2 transcript: (forward primer: 5'-CGAAAGGTGCTGGGCAGCTCCGG-3', and reverse primer 5'-CCATTTCCTAGGTCTGCCTCTTG-3', corresponding to nucleotides 739–761 and 1061–1039, respectively). Expression of the GAPDH gene was used as an internal control for the amount of cDNA tested. The specific primers were: forward 5'-ACATGTTCCAATATGATTCC-3' and reverse 5'-TGGACTCCACGACGTACTCA-3' (corresponding to nucleotides 195–215 and 355–335, respectively). The reaction products were analyzed on a 2% agarose gel, and transferred to GeneScreen plus nylon membranes (DuPont, Boston, MA). The membranes were hybridized with a HMGA2 cDNA probe. cDNA probes obtained by PCR were labeled with [32P]dCTP using the random oligonucleotide primers (Ready-To-Go, Pharmacia) at a specific activity of 
7 x 108 cpm/µg.
Protein Extraction, Western Blotting, and Antibodies.
Protein samples from normal pituitary gland and from pituitary adenomas were extracted using TRI-reagent solution (Molecular Research Center, Cincinnati, OH) according to the manufacturer’s protocol. Protein concentration was estimated by a modified Bradford assay (Bio-Rad). The antibodies directed against the HMGA2 protein are described elsewhere (36)
. The protein extracts were boiled in Laemmli sample buffer, separated by SDS-PAGE and transferred to Immobilon-P transfer membranes (Millipore). Membranes were blocked with 5% nonfat milk proteins and incubated with the antibody at the appropriate dilution. Bound antibodies were detected by the horseradish peroxidaseconjugated secondary antibodies followed by enhanced chemiluminescence (Amersham). As a control for equal loading of protein lysates, the blotted proteins were probed with antibodies against 
-tubulin.
Immunohistochemical Analysis of HMGA2 Expression.
For the immunohistochemical studies of paraffin-embedded samples, 5–6-µm-thick paraffin sections were deparaffinized and placed in a solution of absolute methanol and 0.3% hydrogen peroxide for 30 min and washed in PBS before immunoperoxidase staining. Slides were then incubated overnight at 4°C in a humidified chamber with the primary antibodies diluted 1:100 in PBS and subsequently incubated, first with biotinylated goat antirabbit IgG for 20 min (Vectostain ABC kits, Vector Laboratories), and then with premixed reagent ABC (Vector) for 20 min. Immunostaining was performed by incubating slides in diaminobenzidine (DAB-DAKO) solution containing 0.06 mM DAB and 2 mM hydrogen peroxide in 0.05% PBS (pH 7.6) for 5 min; and after chromogen development, slides were washed, dehydrated with alcohol and xylene, and mounted with coverslips using a permanent mounting medium (Permount). Micrographs were taken on Kodak Ektachrome film with a Zeiss photo system. The antibodies used in this study were rabbit polyclonal raised against the recombinant HMGA2 protein. The characterization and specificity of these antibodies is described elsewhere (37)
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, with direct analysis and short-term culture of 11 tumors (9 prolactin-secreting and 2 nonfunctioning secreting pituitary adenomas), a karyotype was defined in 6 prolactin-secreting and in the 2 nonfunctioning secreting pituitary adenomas. An abnormal karyotype was found in the six prolactin-secreting adenomas (cases PA 78, PA 81, PA 83, PA 88, PA 89, and PA 94) successfully processed; these included three cases with chromosome 12 trisomy (PA 78, PA 81, and PA 88) and one case (PA 83) with a der(12) chromosome. Although a karyotype could not be defined in PA 85 and PA 90, a single metaphase showing gain of chromosome 12 was observed in these two cases, whereas because of the paucity of the tumor tissue, we were not able to perform cytogenetic analysis on PA 87 (Table 2)
. No discrepancies were found in cases in which the same tumor was successfully analyzed by both the direct and-short term culture methods.
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shows the results of interphase dual-color FISH that were obtained by counting at least 200 nuclei per each sample using different combinations of HMGA2-specific PAC and BAC probes, and D12Z3-specific alphoid probe. PHA-stimulated lymphocytes from control blood of healthy individuals and two nonfunctioning pituitary adenomas were hybridized in parallel to determine for each probe, both the percentage of nuclei with more or less than two signals and the percentage of nuclei with a split hybridization signal. After cohybridization with the PAC or BAC probes, 94–98% of nuclei from peripheral blood cells and nonfunctioning secreting pituitary adenoma cells appeared as two pairs of red/green overlapping spots (Table 2
; Fig. 1A
).
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. A remarkable percentage of nuclei in four of nine tumors (PA 83, PA 85, PA 90, and PA 94) had more than three hybridization signals, which is witness to the heterogeneity of these tumor cell populations (Table 2
; Fig. 1C
).
We next cohybridized both BAC probes, which encompassed the entire HMGA2 locus, with the chromosome-12 alphoid-specific probe, which on a disomic sample resulted in two paired red-green signals (Fig. 1D)
. This experiment showed that the BAC probes produced a number of spots higher, usually by 1 or 2, than the alphoid probe in a variable percentage of nuclei of six of nine prolactin-secreting adenomas (remarkably high in PA 83, PA 90, and PA 94; less high in PA 81, PA 85, and PA 88; Fig. 1, E and F
; Table 2
).
Because of limited tumor proliferative activity, FISH analysis of metaphases was often precluded. However, in three cases (PA 83, PA 88, and PA 94), a single metaphase hybridized with the BAC combinations was found (Fig. 2)
. Fig. 2A
shows a double-color FISH metaphase from PA 83: eight pairwise green-red hybridization signals appeared on seven chromosomes; one 12-derived marker chromosome displayed double overlapping green-red spots. Interestingly, the same metaphase displayed two small marker chromosomes: one showed both BAC signals, and the other showed only the green signal produced by BAC 669 g18. The entire set of hybridized chromosomes is shown in the inset of Fig. 2A
. A QFQ-banded metaphase is shown in Fig. 2B
; visible are the chromosome resembling the 12-derived marker with double overlapping HMGA2 signals, and the apparently normal chromosome 12.
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, show the same metaphase from PA 88 after double-color FISH with BAC clones and QFQ banding. In the FISH metaphase, besides two chromosomes 12, there is a small marker showing only the signal produced by BAC 698 i6. A single metaphase from PA 94 showed four paired signals resulting from the BAC clones: 2 on the 12 homologues and 2 on a large marker with 3 centromeric constrictions (Fig. 2C)
. Because the morphology and the DAPI and QFQ pattern (Fig. 2F)
of the tricentric marker suggested it might contain chromosome 2, we next used differentially labeled painting probes specific for chromosomes 2 and 12. As shown in Fig. 2F
, the marker chromosome was decorated from pter to qter by the above libraries: the alternated sequence of chromosome 2-derived and chromosome 12-derived regions suggested a complex interchromosomal rearrangement that leads to duplicated insertion of the 12cen-q14–15 region; this was confirmed by FISH analysis with D12Z3 (Fig. 2G)
.
HMGA2 Gene Overexpression in Prolactin-Secreting Adenomas.
To verify whether the cytogenetic alteration found in some prolactinoma samples resulted in HMGA2 induction, we evaluated HMGA2 expression in neoplastic samples by reverse transcription-PCR and by Western blot analysis using antibodies raised against recombinant HMGA2. In some cases the amount of material available was too small to be analyzed.
As shown in Fig. 3A
, an HMGA2-specific mRNA transcript was detected in prolactin-secreting adenomas in samples 83, 85, 87, 88, 90, and 94 but not in samples 78 and 89. No HMGA2 expression was detected in either of the two nonfunctioning secreting pituitary adenoma samples (82 and 86). Neither was HMGA2 expressed in normal pituitary glands, as expected from previous studies with normal adult tissues (14)
. As negative control, we have also used the peripheral blood (Lane PB).
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. In fact, a band of Mr 15,000, corresponding to the HMGA2 protein, was observed in samples 83, 88, and 94, but not in normal pituitary gland nor in the nonfunctioning secreting pituitary adenoma sample 86. Additionally there was a slower migrating band of about Mr 18,000 in sample 88. Interestingly, the specimen 94 appears to have very highly expressed HMGA2 mRNA, yet has protein expression levels similar to other specimens. Immunohistochemistry of the HMGA2 protein confirmed the reverse transcription-PCR and Western blot data. In fact, there was no immunoreactivity in patient 89, and a specific nuclear immunostaining in the pituitary adenomas of patients 83, 85, 88 (Fig. 4)
and 90 (data not shown) was detected.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, is supported by the results of interphase dual FISH with HMGA2 BACs and D12Z3 probe showing, in PA 83, 85, 88, and 94, a higher representation of the HMGA2 region as compared with the centromeric one in a consistent fraction of cells (Table 2)
. At difference of normal pituitary, it is noteworthy that all of these four tumors were found to express HMGA2 mRNA and protein (Fig. 3)
.
Chromosomal rearrangement, disrupting the HMGA2 gene, may also occur, which results in HMGA2 overexpression. Suggestive evidence is provided by the metaphases in PA 83 and PA 88 with a small marker with only one of the two signals expected subsequent to FISH with HMGA2-BACs (Fig. 2, A and C)
. Despite these observations concerning single metaphases, it is not merely a coincidence that, in at least one case (PA 88) of the two tumors showing minute markers with uncoupled signals, there was a rearranged HMGA2 protein of a higher molecular weight (Mr 18,000 versus a normal band of Mr 15,000). This band presumably derives from the fusion of HMGA2 sequences (probably the first three AT hooks) with ectopic sequences as occurs in benign tumors of mesenchymal origin. Unfortunately, because of the small amount of RNA available, we were unable to perform a 3' rapid amplification of cDNA ends (RACE) to clone the fused gene. No HMGA2 expression was detected in PA 89, which lacked the trisomy 12 in the three karyotyped metaphases. Similarly, HMGA2 was undetectable in PA 78, in which there is a gain of the entire chromosome 12 (trisomy), but the gain of the chromosome 12 is not accompanied by overrepresentation of HMGA2 region, as indicated by the balance between D12Z3 and BAC signals. We favor the view that the gain of chromosome 12 is an early event in prolactin-secreting adenoma oncogenesis, necessary, but not sufficient, to drive increased HMGA2 expression that results from the amplification of the 12q14–15 region.
The number of patients with prolactinomas included in this study is too small to draw definitive conclusions about correlations between HMGA2 overexpression and clinical features. However, it is interesting to note that the five prolactinomas bearing specific HMGA2 mRNA transcripts (cases PA 83, 85, 87, 88, and 94) were highly resistant to dopaminergic drugs. Differently, prolactinomas 78 and 89, in which HMGA2 mRNA transcripts were not overexpressed, were a more heterogeneous group. Therefore, it seems that HMGA2 overexpression is more frequently found in tumors with a high degree of resistance to dopaminergic agents. Interestingly, nonresponse to dopaminergic agents is associated with a more aggressive behavior in vivo and in vitro (37 , 26) .
The results of this study suggest that HMGA2 overexpression, a finding shared by several human malignant neoplasias (18, 19, 20, 21, 22, 23, 24, 25) , is also associated with the human prolactin-secreting adenomas, and might, thus, have a role in the generation of these benign neoplasias. This hypothesis is consistent with the development of mixed growth hormone cell/prolactin cell pituitary adenomas in transgenic mice, carrying the wild-type and truncated HMGA2.4
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by grants from Associazione Italiana Ricerca sul Cancro (Progetto Speciale Oncosoppressori), the Progetto Finalizzato "Biotecnologie" of the Consiglio Nazionale delle Ricerche (CNR), the Ministero dell’Università e Ricerca Scientifica e Tecnologica (MURST) projects "Terapie antineoplastiche innovative" and "Piani di Potenziamento della Rete Scientifica e Tecnologica"; and by the Ministero della Sanità and the Associazione Partenopea per le Ricerche Oncologicalhe (APRO). G. M. P. is supported by a Fondazione Italiana per la Ricerca sul Cancro (FIRC) fellowship. The Istituto Auxologico Italiano (IRCCS) is supported by a grant from the Ministero della Sanità. 
2 To whom requests for reprints should be addressed, at Dipartimento di Biologia e Genetica per le Scienze Mediche, Via Viotti, 3/4, 20133 Milan, Italy. Phone: 39-02-50315859; Fax: 39-02-50315864; E-mail: lidia.larizza{at}unimi.it
3 The abbreviations used are: ACTH, adrenocorticotropic hormone; FISH, fluorescence in situ hybridization; DAPI, 4',6-diamidino-2-phenylindole; BAC, bacterial artificial chromosome; PAC, P1 artificial chromosome.
4 M. Fedele, S. Battista, L. Kenyon, G. Baldassarre, V. Fidanza, A. J. Klein-Szanto, A. F. Parlow, R. Visone, G. M. Pierantoni, E. Outwater, M. Santoro, C. M. Croce, and A. Fusco. Overexpression of the HMGA2 gene induces the onset of pituitary adenomas by impairment of the RB/E2F pathway, submitted for publication.
Received 7/27/01. Accepted 2/14/02.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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satellite DNA subset specific for chromosome 12. Am. J. Hum. Genet., 46: 784-788, 1990.[Medline]
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