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Divisions of Reproductive and Pediatric Endocrinology (M.H.B., B.M., K.R., P.C.W.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032; Division of Endocrinology (F.M., G.A.), University of Padua, Padua 35100, Italy; Division of Medical Sciences (P.M.S., I.B.), University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, United Kingdom; and Department of Physiology (W.E.R.), Medical College of Georgia, Augusta, Georgia 30912
Address all correspondence and requests for reprints to: Dr. William E. Rainey, Department of Physiology, Medical College of Georgia, 1120 15th Street CA3094, Augusta, Georgia 30912. E-mail: wrainey{at}mcg.edu.
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Abstract |
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Objective: The objective of this study was to compare the expression profiles of several steroid-metabolizing enzymes and transcription factors from normal adrenal (NA), APAs, and CPAs.
Design: RNA from NAs, APAs, and CPAs were analyzed by microarray and real-time RT-PCR.
Setting: This study was performed at academic research laboratories.
Patients: At least nine normal controls and 12 patients with APA or CPA were studied.
Intervention: There was no intervention procedure.
Main Outcome Measure: The main outcome measure was the expression of steroidogenic enzymes in adrenocortical disease.
Results: A microarray indicated a greater than 3-fold increase in the expression of CYP11B2 (aldosterone synthase) in APA, whereas 11ß-hydroxysteroid dehydrogenase type 2 (HSD11B2) and HSD17B1 had greater than 3-fold increases in expression in CPA compared with NA. Real-time RT-PCR showed that APAs produced higher levels of HSD3B2, CYP21 (21-hydroxylase), and CYP11B2 mRNA, whereas CPAs produced higher levels of CYP11A (cholesterol side-chain cleavage), CYP17 (17
-hydroxylase/17–20 lyase), HSD3B2, and CYP11B1 (11ß-hydroxylase) mRNA compared with normal adrenal. Steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome gene 1), and GATA-6 were expressed at higher levels in APAs and CPAs, whereas NURR1 was expressed at higher levels in APAs than in CPAs or NAs.
Conclusion: Elevated production of aldosterone in APAs and of cortisol in CPAs is associated with increased expression of enzymes needed for corticosteroid production along with alterations in transcription factors that enhance the expression of steroid-metabolizing enzymes.
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Introduction |
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The mechanisms leading to the autonomous hypersecretion of aldosterone or cortisol in APAs or CPAs have not been defined. However, several studies have demonstrated that APAs maintain angiotensin II receptors and steroid-metabolizing enzymes, including CYP11B2 (7, 8, 9, 10, 11, 12). Likewise, most CPAs are characterized by overexpression of CYP17, CYP21, and possibly CYP11B1, steroidogenic enzymes that are required for cortisol production (4, 8, 12, 13). Thus, the overproduction of steroid hormones in adrenal cortical tumors may result in part from the disordered expression of steroidogenic enzymes.
In this study we used high-density oligonucleotide microarray and real-time RT-PCR analyses of normal adrenal, APA, and CPA to compare the expression profiles of steroid-metabolizing enzymes involved in adrenal steroidogenesis. We also used real-time RT-PCR to examine the expression profiles of six transcription factors known to regulate steroid-metabolizing enzyme transcription. Molecular insights into the causes of excess production of these major steroid hormones should lead to a clearer understanding of the mechanisms regulating the production of these hormones under normal conditions.
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Materials and Methods |
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Human adrenal glands were obtained from the Cooperative Human Tissue Network (Philadelphia, PA) and from Dr. Franco Mantero (Division of Endocrinology, University of Padua Medical School, Padua, Italy). All samples were obtained with full university approval, and written informed consent was obtained from each patient.
Microarray analysis
Samples of total RNA from normal adult adrenal, APAs, and CPAs were used to make four pools each of normal and adenoma RNA (three tissue samples per pool). These RNA pools were then hybridized to an Affymetrix human HG-U133A and B oligonucleotide two-microarray set containing more than 44,000 probe sets representing over 33,000 human genes (Affymetrix, Santa Clara, CA). The arrays were scanned at high resolution using an Affymetrix GeneChip Scanner 3000 located at the University of Texas Southwestern microarray core facility. Results were analyzed using GeneSpring version 6.1 software (Silicon Genetics, Redwood City, CA) to identify genotypic differences among normal adult adrenal, APAs, and CPAs.
RNA extraction and real-time RT-PCR
RNA extraction and real-time RT-PCR were carried out as previously described with modifications (14). The purity and integrity of the RNA were checked spectroscopically and by gel electrophoresis before use. Primers and probes used for real-time RT-PCR were previously described (14, 15, 16). For steroidogenic acute regulatory protein (StAR), CYP11A, CYP21, cytochrome b5 (CYb5), nerve growth factor-induced clone B (NGFIB), NURR1, GATA-4, and GATA-6 quantitation, a double-stranded DNA dye, SYBR Green I (Molecular Probes, Eugene, OR) was used along with 15 µl 2x SYBR Green Universal PCR MasterMix (Applied Biosystems, Foster City, CA) and 100 nM of each primer. For steroidogenic factor-1 (SF-1) and DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X-chromosome gene 1), SYBR Green I was used along with 50 nM of each primer. 11ß-Hydroxysteroid dehydrogenase type 2 (HSD3B2), CYP17, CYP11B1, CYP11B2, and 18S quantitation was performed using a TaqMan ribosomal RNA reagent kit (Applied Biosystems) and 10 µl primer/probe mix. For most TaqMan reactions, the final concentrations of primer and probe used were 100 nM each. However, for HSD3B2, the final concentrations of primer and probe used were 400 and 200 nM, respectively. For 18S, the final concentrations of primer and probe were 50 and 100 nM, respectively. Standard curve cDNA plasmids for 18S and all steroidogenic enzymes and transcription factors were used to quantify transcript levels. As an internal control, each individual sample was normalized to its 18S ribosomal RNA content, and mRNA levels were expressed as attomoles per microgram of 18S rRNA.
Statistical analysis
Statistical analysis of microarray data was performed using the paired t test. Real-time RT-PCR data analysis was performed using ANOVA; all pairwise multiple comparison procedures were performed with the Student-Newman-Keuls method. Statistical analyses were carried out with SigmaStat 3.0 software. P < 0.05 was considered significant.
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Results |
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We used oligonucleotide microarrays to examine the transcript profile of 42 steroid-metabolizing enzymes from normal adrenal gland (NA), aldosterone-producing adenomas (APAs) and cortisol-producing adenomas (CPAs). Samples of total RNA were used to make four pools each of normal and adenoma RNA (three samples per pool). Gene profiling was performed using 12 independent arrays and was analyzed using GeneSpring software. Representative microarrays are shown that compare the mRNA expression of one APA pool (Fig. 1
) and one CPA pool (Fig. 2) vs. NA mRNA. The microarray results are also presented as pooled data from all microarray experiments (Tables 1 and 2). Tables 1 and 2 are further divided into high-expressed and low-expressed genes. Results from the pooled data show that only one transcript among the highly expressed genes, CYP11B2 (aldosterone synthase), has a greater than 3-fold increase in expression between APA and normal adrenal (Table 1). HSD11B2 and HSD17B1, both in the category of low-expressed genes, were found to have a greater than 3-fold increase in expression between CPA and NA (Table 2). In confirmation of the microarray results, real-time RT-PCR analysis detected a significant 3.4-fold increase in HSD11B2 transcript in CPA, but not in APA, vs. NA (data not shown).
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To confirm our microarray results and to gain additional insight into the pathophysiology of adrenal steroidogenesis that is characteristic of APA and CPA, we quantified the mRNA expression of eight genes involved in adrenal steroid production of aldosterone and cortisol by real-time RT-PCR. A summary of the steroidogenic pathways for the production of aldosterone and cortisol in the human NA cortex is shown in Fig. 3.
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The movement of cholesterol into the inner mitochondrial membrane is mediated by increased expression of StAR protein (17). Once inside the mitochondria, cholesterol binds to CYP11A and is cleaved to pregnenolone. Cholesterol transport and cleavage are common to both aldosterone and cortisol biosynthesis. The transcript levels of StAR mRNA were relatively abundant in all samples tested, with a trend for elevated levels in the tumors, whereas the transcript levels of CYP11A mRNA were significantly increased in CPA, but not in APA, vs. NA (Fig. 4A).
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CYP17 converts pregnenolone or progesterone to 17-hydroxypregnenolone or 17-hydroxyprogesterone, respectively (Fig. 3
). The CYP17 protein carries out both 17-hydroxylase and 17,20 lyase activities and is required for cortisol, but not aldosterone, biosynthesis. CYb5 preferentially enhances the activity of CYP17 and, particularly, its 17,20-lyase activity (18). Although the levels of CYP17 mRNA were high in all samples tested, there was a significant increase in transcript in the CPA samples compared with NA (Fig. 4B). However, in contrast with the CYP17 results, low levels of CYb5 mRNA were detected in NA, APA, and CPA, and no significant differences were observed in any of the samples tested (Fig. 4B).
HSD3B2 and CYP21
HSD3B2 converts pregnenolone or 17-hydroxypregnenolone to progesterone or 17-hydroxyprogesterone, respectively. As a consequence, precursors are removed from the 
5 pathway, leading to dehydroepiandrosterone/dehydroepiandrosterone sulfate, and are available for aldosterone and cortisol biosynthesis. CYP21, which converts progesterone or 17-hydroxyprogesterone to deoxycorticosterone or deoxycortisol, respectively, is also required for aldosterone and cortisol production. Levels of HSD3B2 mRNA were significantly higher in APA and CPA than in NA, whereas transcript levels of CYP21 mRNA were increased in APA, but not in CPA, vs. normal adrenal (Fig. 4C).
CYP11B1 and CYP11B2
The final steps in the biosynthesis of cortisol and aldosterone in the human adrenal cortex rely on the expression of two unique isozymes, CYP11B1 and CYP11B2, respectively (Fig. 3). CYP11B2, which converts deoxycorticosterone to aldosterone, is expressed only within the adrenal zona glomerulosa (19, 20, 21). CYP11B1 transcript was abundant in all samples tested, with increased levels of transcript in CPA over that seen in NA (Fig. 5). In contrast, very low levels of CYP11B2 mRNA were detected in NA and CPA samples (Fig. 5). However, as expected, CYP11B2 expression was high in the APA samples.
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Excess production of steroid hormones in adrenal cortical tumors may be due to the disordered expression of genes encoding steroid-metabolizing enzymes. Therefore, we examined the expression profiles of six transcription factors that are known to regulate steroidogenic enzymes.
NGFIB and NURR1
In the human adrenal gland, the NGFIB family of orphan nuclear receptors has been implicated in the transcriptional regulation of select steroidogenic enzymes. We examined the mRNA expression of NGFIB (NR4A1) and NURR1 (NR4A2) in normal adrenals, APAs, and CPAs by real-time RT-PCR (Fig. 6A). Levels of NGFIB mRNA were somewhat similar in APA and CPA compared with NA, although there was a trend for elevated levels in APAs and reduced levels in CPAs. In contrast, levels of NURR1 mRNA were significantly increased in APA over those in NA and CPA, with a trend toward reduced levels in CPA vs. NA.
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We also examined adenoma samples for the presence/absence of SF-1 (NR5A1) and DAX-1 (NR0B1), two orphan receptors that colocalize in the adrenal and have been widely implicated in the transcriptional regulation of several steroidogenic genes, including StAR, CYP11A, CYP17, and CYP11B2. Levels of SF-1 mRNA were relatively abundant in all samples tested, but were higher in APA and CPA than in NA (Fig. 6B). Levels of DAX-1 mRNA were also increased in APA and CPA over those in NA (Fig. 6B). However, transcript levels of DAX-1 in the various samples were approximately 10- to 40-fold lower than those observed for SF-1.
GATA-4 and GATA-6
GATA-4 and GATA-6 have been detected in human NA, where both transcription factors have been proposed as modulators of CYP17 gene activity (16, 22, 23, 24). We thus examined GATA-4 and GATA-6 mRNA expression in NA, APA, and CPA to determine whether either transcription factor was associated with abnormal steroid hormone production. Levels of GATA-4 mRNA were somewhat similar in APA and CPA compared with NA, although there was a trend for elevated levels in APAs (Fig. 6C). However, transcript levels of GATA-4 were barely detectable in the samples tested. Transcript levels for GATA-6 ranged from approximately 5- to 20-fold higher than those for GATA-4 (Fig. 6C). Additionally, in contrast with the results from GATA-4 real-time analysis, GATA-6 transcript levels were significantly increased in APA and CPA over those in NA.
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Discussion |
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Microarray analysis of steroid-metabolizing enzymes
As expected, our composite microarray results demonstrated that CYP11B2 was expressed at more than 30-fold higher levels in APAs compared with NA. These results are consistent with the increased production of aldosterone characteristic of APAs. Other steroid-metabolizing enzymes, including HSD11B2 and HSD17B1, were expressed at elevated levels in CPAs (15- and 4.77-fold, respectively). In contrast with our findings, a previous study by Mune et al. (25), which examined the expression of HSD11B2 in CPAs, found that expression was inversely correlated with cortisol secretion. Likewise, a more recent study that measured the plasma cortisol/cortisone ratio in adenomas vs. NA found that patients with CPA had lower HSD11B2 activity, whereas HSD11B2 activity in patients with APA was increased (26). However, our real-time RT-PCR for HSD11B2 detected elevated levels of this enzyme in CPA (P = 0.002), but not in APA, compared with NA samples (n = 12 for each sample group).
Gene profiling of human tumors has become a useful tool in the identification of genes involved in tumor classification and progression (27). For example, DNA microarrays were used by Giordano et al. (28) to examine transcripts from adrenocortical carcinomas, adenomas, and NA. Although no differences in gene expression between NA cortex and adrenocortical adenomas were found, these investigators reported that IGF-II and other growth factors were up-regulated in adrenocortical cancer. More recently, DNA microarrays of human adrenocortical tumors were employed by de Fraipont et al. (29) to identify two gene clusters involved in oncogenesis (the IGF-II cluster) or steroidogenesis. Interestingly, the steroidogenesis cluster, which included StAR, CYP11A, CYP17, CYP21, CYP11B1, and HSD3B2, was expressed at a high level in a group of glucocorticoid-secreting tumors. Furthermore, both gene clusters were found to be reliable predictors of tumor malignancy.
Microarrays vs. real-time RT-PCR
Overall, the composite microarray results, which were calculated from 12 tissue samples used to generate three separate array experiments, are in general agreement with the results obtained from real-time RT-PCR. However, real-time RT-PCR is apparently a much more sensitive measure of actual differences between samples. For example, CYP17 and CYP11B1 are essential for cortisol production. However, our microarray studies show similar levels of both CYP17 and CYP11B1 transcript in CPA vs. NA (0.69 ± 0.03 and 0.79 ± 0.04, respectively). Conversely, our real-time results show 1.83- and 2.34-fold increases in CYP17 and CYP11B1 transcript levels, respectively, over those found in NA, and these fold differences are significant. Thus, our real-time data are more consistent with the higher utilization of these enzymes in excess cortisol production.
Steroidogenic enzyme expression profiles in APA predict increased aldosterone production, whereas expression profiles in CPA predict increased cortisol production
The overproduction of steroid hormones in adrenal cortical tumors may result from the disordered expression of steroidogenic enzymes. For example, overexpression of CYP11B2 and CYP17 in APA and CPA, respectively, has been widely reported in the literature and confirmed by our results (4, 8, 9, 12, 13). However, some previous studies that examined the presence of steroidogenic enzymes in various types of adrenal adenomas have produced conflicting results. These discrepancies may in part be due to the sensitivity of the detection methods used. An early study, using Northern analysis on tissue samples from three Cushing’s patients, found elevated expression of CYP17, but similar levels of CYP21, CYP11A, and CYP11B1 mRNA, compared with NA (13). In contrast, a more recent in situ hybridization study found that CYP17 and CYP11B1 were high in CPA and low in APA samples (8). Additionally, positive correlations between expression of CYP17 and cortisol secretion and between CYP11B1 and CYP17 levels have been reported (4). Fallo et al. (9) examined select steroid-metabolizing enzymes present in APAs by real-time RT-PCR and found elevated levels of CYP11B2 and reduced levels of CYP11B1 transcript. In contrast to our findings, Fallo’s group (9) reported that CYP17 levels were similar in APAs compared with NA and that the measured levels of CYP11B1 and CYP11B2 transcript in the adenoma samples were very low.
From both our study and that by Fallo et al. (9), it appears that it is the expression of CYP11B2 mRNA that shows the most dramatic change in the APA steroidogenic enzyme profile. Preliminary analysis of several incidentaloma RNA samples have shown that none has elevated CYP11B2 (data not shown). Thus, the expression of CYP11B2 appears to be a marker for APA vs. CPA and incidentaloma. However, whether elevated expression of CYP11B2 results in hyperaldosteronism is not completely clear.
It has long been known that the production of aldosterone appears to have two rate-limiting steps. The first, or early step, regulates cholesterol transport and is controlled by the StAR protein, whereas the late step is regulated by CYP11B2. Therefore, the adrenal cell needs both StAR and CYP11B2 for normal regulation of aldosterone production. As suggested by our studies of StAR mRNA, most tumors (both APA and CPA) maintain StAR expression, whereas only the APA expresses high levels of CYP11B2. It is unclear whether the expression of CYP11B2 (without high StAR) would lead to hyperaldosteronism. It should be noted that relatively small amounts of aldosterone are needed to maintain normal salt balance (500-fold less that that of cortisol). Indeed, the precursor for aldosterone, corticosterone, is normally produced and released from the fasciculata at levels that would cause severe hypertension if it were converted to aldosterone. Even in the absence of elevated StAR, an adenoma could use corticosterone from the surrounding normal tissue or from the circulation to produce aldosterone. However, the expression of mRNA for StAR would suggest that both CPA and APA can use cellular cholesterol to product cortisol and aldosterone, respectively.
Transcription factors that regulate steroidogenic genes
Several orphan nuclear receptors and transcription factors, including those of the NGFIB and GATA families as well as SF-1 and DAX-1, have been shown to regulate the transcription of steroid-metabolizing enzymes. The NGFIB family of orphan nuclear receptors, which includes NGFIB (NR4A1), NURR1 (NR4A2), and NOR1 (NR4A3), plays an important role in the coordinated regulation of the hypothalamic/pituitary/adrenal axis. In the adrenal gland, NGFIB may regulate CYP21 and HSD3B2 transcription, whereas NURR1 is an important regulator of the CYP11B2 gene (14, 30, 31, 32). Recently, Lu et al. (33) examined the expression pattern of NURR1 and related family members in normal and diseased adrenal glands by immunohistochemistry. NURR1 immunoreactivity was detected in the nuclei of zona glomerulosa cells in all age groups examined and was higher in APAs than in CPAs. The results of this recent study also demonstrated the close association between NURR1 and CYP11B2 in human adrenal glands.
With the apparent exception of CYP11B2, all the steroidogenic genes involved in aldosterone and cortisol production are positively regulated by SF-1 (34, 35, 36, 37, 38, 39, 40, 41, 42). Previous studies have reported that SF-1 protein and mRNA levels remain relatively stable between NA and APA and CPA samples (43, 44). However, we found that levels of SF-1 mRNA were higher in APA and CPA than in NA. Although the cause of this discrepancy is unclear, it is possible that high expression of SF-1 protein in adenoma samples could explain the resulting increase in steroid hydroxylase activity and steroid production present in APAs and CPAs. Support for this line of reasoning comes from a recent study of childhood adrenocortical tumors that found increased copy number of the SF-1 gene in three of four Cushing’s carcinomas and in three of three adenomas of undefined type (45).
The orphan receptor DAX-1 is a known repressor of SF-1 transactivation of CYP17, an enzyme specifically required for cortisol, but not aldosterone, production (34, 46). In NA, SF-1 and DAX-1 colocalize in the zona glomerulosa, fasciculata, and reticularis, which indicates that these factors may physically interact to prevent SF-1 binding to and activation of selected genes (43). DAX-1 expression is reported to be low or absent in APAs (47). Recently, it was reported that DAX-1 expression levels were significantly decreased in CPAs, resulting in the up-regulation of CYP17 (44). In contrast to these published reports, our results showed elevated levels of both SF-1 and DAX-1 in the APA and CPA samples compared with NA tissue. It is possible that there is complex interplay between SF-1 and DAX-1, and that the SF-1/DAX-1 ratio in the various adrenal zones may be important in regulating adrenal steroid hormone production.
Evidence suggests that GATA-4 and GATA-6 are involved in adrenal cortisol and androgen production through the regulation of the genes encoding CYP17 and/or steroid sulfotransferase 2A1 (officially designated SULT2A1) (16, 22, 23, 24). GATA-4 and GATA-6 transcription factors are present in human fetal adrenal gland, whereas GATA-6, but not GATA-4, expression has been detected in the reticularis and fasciculata of adult adrenal cortex (16). In this study we were able to discern the presence of GATA-4 in normal adult adrenal and in our adenoma samples. However, detection was close to the limits of our real-time RT-PCR capability. In a recent report GATA-4 was detected in only one of six APAs and in three of five CPAs, suggesting that it is more closely associated with cortisol than with aldosterone production (48). Our results also showed elevated levels of GATA-6 in the CPA samples, which is in keeping with a role for this transcription factor in adrenal cortisol and androgen production. However, we also detected elevated levels of GATA-6 in the APA samples. The significance of this finding is not yet known, but we have found that GATA-6 can increase HSD3B2 transcription (data not shown).
In this study we have shown that the excess production of steroid hormones characteristic of APAs and CPAs is associated with increased production of specific steroidogenic enzymes. Additionally, due to the increased expression of NURR1 in APAs, it is likely that this transcription factor is partially responsible for the elevated levels of aldosterone production found in these adrenal tumors. Likewise, the increased production of GATA-6 and its corresponding effect on the production of CYP17 could account for the increased production of cortisol that is characteristic of CPAs.
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Footnotes |
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First Published Online June 28, 2005
Abbreviations: APA, Aldosterone-producing adenoma; CPA, cortisol-producing adenoma; CYb5, cytochrome b5; DAX-1, dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X-chromosome gene 1; HSD11B2, 11ß-hydroxysteroid dehydrogenase type 2; NA, normal adrenal; NGFIB, nerve growth factor-induced clone B; SF-1, steroidogenic factor-1; StAR, steroidogenic acute regulatory protein.
Received April 18, 2005.
Accepted June 21, 2005.
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References |
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-hydroxylase (P-450c17) mRNA in adrenocortical adenomas from patients with Cushing’s syndrome. Mol Cell Endocrinol 80:83–89[CrossRef][Medline]
5-4 isomerase promoter by the transcription factor steroidogenic factor-1/adrenal 4-binding protein and phorbol ester. J Biol Chem 272:7960–7967This article has been cited by other articles:
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