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Original Studies |
, Pit-1, Gi2, and Somatostatin Receptor 2 in Human Somatotroph Adenomas: Involvement in Octreotide Sensitivity1
Interactions Cellulaires Neuroendocriniennes, UMR 6544, Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Jean Roche, Faculté de Médecine Nord (A.B., I.P.-B., G.G., A.J.Z., P.J., A.E.), 13916 Marseille Cedex 20; Service d’Endocrinologie, Centre Hospitalo-Universitaire Timone (P.J.), 13385 Marseille, France
Address all correspondence and requests for reprints to: Dr. Anne Barlier, Interactions Cellulaires Neuroendocriniennes, UMR 6544, Centre National de la Recherche Scientifique, Université de la Méditerranée, Institut Fédératif Jean Roche, Faculté de Médecine Nord, boulevard P. Dramard, 13916 Marseille Cedex 20, France. E-mail: barlier.a{at}jean-roche.univ-mrs.fr
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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, Pit-1,
Gi2, and SSTR2, involved in the regulation of secretory
activity in somatotroph cells, were assessed by Northern blot. A
decreased expression of the Gs gene was found in
gsp+ tumors, suggesting the existence of a negative
feedback of the oncogenic protein upon its own messenger ribonucleic
acid (mRNA). In contrast, Gi2, Pit-1, and GH messengers
were not significantly different in the groups. A positive correlation
between the in vitro and in vivo GH
octreotide-induced secretory inhibition and the expression of SSTR2
mRNA was found. However, the expression of the gene for SSTR2 appeared
not to be different between gsp+ and
gsp-, even when the octreotide sensitivity was
significantly higher in the adenomas carrying the mutation.
Interestingly, the SSTR2 gene expression was significantly correlated
to those of Gi2 and Pit-1. In the same way, the
Gs mRNA expression was positively correlated with those
of Gi2 and Pit-1. Such correlations strongly suggest a
concerted dysregulation of the expression of these genes in both
categories of adenomas. The loss of the octreotide sensitivity
represents one aspect of the dysregulation process that partially
results from the decreased SSTR2 expression. However, the improvement
of the sensitivity associated with the presence of the
gsp oncogene seems to proceed in a way different from
SSTR2 expression. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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protein, thus leading to a constitutive
activation of the adenyl cyclase (7). Several studies failed to
determine a clinical specific phenotype related to the gsp
mutation (4, 5, 6, 8, 9). In the GH3 or GC pituitary cell
line, an impact of the gsp oncogene on the expression of
genes coding for the transcription factor Pit-1 and for GH has been
demonstrated (9, 10, 11). However, the impact of gsp oncogene on
gene expressions is still poorly understood in human adenomas.
GH hypersecretion present in somatotroph adenomas can be inhibited by
somatostatin agonists such as octreotide or lanreotide. Awkwardly,
serum GH and insulin-like growth factor I levels reach normal values in
only 50% of treated patients (12). The molecular mechanisms
controlling somatostatin sensitivity are incompletely understood. Some
studies have suggested that tumors with the gsp oncogene (8, 9, 13) or with high adenylate cyclase activity (14) displayed a better
sensitivity to somatostatin. In fact, we have shown that the
Gs mutation could be a marker of the
susceptibility of the tumor to be controlled by octreotide (6). The
mechanisms by which the gsp oncogene improves sensitivity
have not been identified, although the expression of somatostatin
receptor (SSTR) could play an important role. It is well known that the
resistance to dopamine agonists in prolactinomas is partially due to a
decreased expression of the D2 receptor (15, 16). Moreover, in
dopamine-resistant prolactinomas, decreased expressions of the
messengers for Pit-1 and Gi2 were observed (16, 17);
both proteins are involved in the dopaminergic transduction pathway. It
is therefore likely that the same type of alteration could be
responsible for somatostatin unresponsiveness in somatotroph adenomas.
The two somatostatin agonists preferentially employed in acromegaly,
octreotide and lanreotide, display a higher affinity for the SSTR2
subtype. In addition, postreceptor anomalies touching proteins involved
in SSTR2 transduction pathways, such as Gi2 and Pit-1
(for review, see Ref. 18), may also contribute to the somatostatin
unresponsiveness.
In the present study, a series of 24 somatotroph adenomas presenting
with variable sensitivity to octreotide and bearing, or not, the
gsp oncogene was compared. Our first aim was to examine the
impact of gsp oncogene on the expression of the genes coding
for Gs, Gi2, Pit-1, and SSTR2. Secondly,
we asked whether changes in the expression of some of these genes could
alter the sensitivity to octreotide. In this study, a lower expression
of Gs gene in gsp+ tumors was found. The
decreased sensitivity to the somatostatin agonist was shown to be
related at least in part to a lower expression of the SSTR2 gene.
However, this expression was not higher in the gsp+ group.
Finally, we found a coordinated decrease in the expression of the genes
coding for all those proteins; all of them were implicated in the
differentiation and the regulation of secretory activity of somatotroph
cells.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study was approved by the ethics committee of the
University of Aix-Marseille (France) and was undertaken after informed
consent was obtained from each patient and all participants.
Twenty-four acromegalic patients, aged 24–67 yr, were selected. The
endocrine status and the characterization of the tumors were determined
previous to treatment (Table 1
). The
basal GH and PRL levels were measured using commercial kits
(Immunotech, Marseilles, France; Medgenix Diagnosis,
Fleurus, Belgium) and expressed as the mean GH or PRL plasma levels
obtained hourly for 6 h. Sizes and extent of pituitary tumors were
evaluated by magnetic resonance imaging. The evaluation of in
vivo octreotide sensitivity was performed as follows. After a
single 100-µg sc injection of octreotide (Sandostatin,
Novartis, Basel, Switzerland), blood samples were withdrawn every hour
for 6 h to measure GH plasma concentrations. The GH inhibition was
represented by the difference between basal GH values and the mean GH
levels between 2–6 h after administration of the drug and was reported
as a percentage of the basal level.
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Immediately after transphenoidal ablation, each tumor was
collected and divided into three parts: one was used for
immunocytochemical analysis, another was used for cell culture, and the
third was frozen at -80 C for subsequent detection of gsp
mutations and quantification of Gs, Gi2,
Pit-1, SSTR2, and GH messenger ribonucleic acids (mRNAs). The methods
for histopathological analyses have been previously described (6). The
immunostaining was positive for GH in all tumors and for PRL and
-subunit glycoprotein in some of them (Table 1
) and was negative for
FSHß, LHß, TSHß, and ACTH in all of them. Those tumors previously
found to contain labeled cells for FSHß, LHß, TSHß, and ACTH were
excluded from the series presented here.
Detection of Gs mutations
Total RNA extraction, RT-PCR amplification of Gs,
and direct sequence analysis of the Gs PCR product were
performed on each tumoral fragment for identification of the
gsp mutation (for details, see Ref. 6). Eight adenomas
presented the mutation. In all cases, Arg was substituted for Cys,
reflecting a CGT to TGT mutation.
Cell culture studies
After mechanical and enzymatic dissociation, 3–5 x 105 cells were plated on coated culture wells (19). Cells were cultured in serum-free medium for 24 h with or without a maximal (10-8 mol/L) concentration of octreotide. The culture media were then collected and stored frozen for GH measurement (6). The effects of the drug were tested in quadruplicate.
Northern blot analysis
Northern blot were performed using 20 µg total RNA (20). The
Gs, Gi2, Pit-1, SSTR2, and GH mRNAs were
measured with complementary DNA (cDNA) probes. The S26 ribosomal mRNA
was used as a control to render results independent from variations in
sample concentration (21). The lack of contamination by normal
pituitary tissue was controlled by hybridization with an oligoprobe
complementary to the human POMC cDNA (16). All of the tumors in which
hybridization with this probe yielded a positive signal were excluded
from our series. A human cDNA coding for the Gs short
isoform and cloned in PT7–7 in the ClaI site was provided
by Dr. Juan Codina (Baylor College of Medicine, Houston, TX). One cDNA
fragment (1.3 kb) was generated by NcoI/HindIII
digestion and used as a probe. The probes specific for human SSTR2 (22)
and S26 were provided by Dr. L. Ouafik (Institute
Jean-Roche, Marseille, France), and the probe for human GH
was provided by Dr. J. Martial (Chemistry Institute B6, University of
Liege, Liege, Belgium). Pit-1 mRNA was identified using a Pit-1 human
cDNA probe generated by PCR from a normal pituitary and spanning the
entire coding region (20). Human cDNA probe specific to
Gi2 mRNAs was obtained by RT-PCR from normal human
pituitary tissue. The PCR was performed using Goldstar DNA polymerase
(Eurogentec, Seraing, Belgium) at 55 C annealing temperature with a set
of primers chosen according to the published sequence (23) in a
specific region, not containing homologous sequence to other
-subunits of G protein (5'-CGCTCTAAGATGATCGACAAGAACCTG-3' and
5'-AGAAGAGGCCGCAGTCCTTCAGGTTGT-3'). The PCR product was of the expected
size (1024 bp) and was confirmed by restriction analysis using the
enzymes StuI and BamHI that gave DNA fragments
corresponding to the specific sequence of Gi2. All of
the cDNA probes were labelled with [-32P]deoxy (d)-CTP
using the T7 Quick-Prime kit (Pharmacia, St. Quentin en Yvelines,
France). Prehybridization was performed at 42 C for 4 h in 50%
formamide, 6 x SSC (standard saline citrate), 5 x
Denhardt’s solution, 0.5% SDS, and 100 µg/mL denatured salmon sperm
DNA. Hybridization was performed in the same buffer for 16 h at 42
C, and the blots were washed at 60 C with 0.1 x SSC-0.1% SDS.
Hybridization buffer (1 x 106 cpm/mL) was used for
Gs, GH, and S26 hybridizations, and 2 x
106 cpm/mL were used for SSTR2, Pit-1, and
Gi2. To obtain complete decay of the radioactive signal,
a period of 2 weeks was allowed between two consecutive hybridizations;
the blots were conserved at -20 C. The blots were successively
hybridized with Gs or SSTR2 and GH cDNA probes,
stripped, hybridized with Pit-1 and S26 cDNA probes, stripped again,
and hybridized with the Gi2 cDNA probe. The ß emission
from 32P of the cDNA probes hybridized on the blot was
directly measured in counts per mm using the GS 363 Molecular Imager
apparatus (Bio-Rad Laboratories, Inc., Richmond, CA) and
Molecular Analyst software. Preliminary assessment of the signal
intensity indicated that blots should be exposed in a phosphor screen
for 2 days for the SSTR2, Pit-1, and Gi2 probes,
overnight for the Gs and S26 probes, and for 3 h
for the GH probe. The amounts of mRNA of all examined genes were
rated to the amount of S26 mRNA measured on the same blot in
each lane. The tumors presented in the Figs. 1 and 4 were chosen
haphazardly according to the availability of the frozen tissue.
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The percentages of secretory responses are presented as the mean ± SE. The statistical significance between two unpaired groups was determined by the Mann-Whitney test. To measure the strength of association between pairs of variables without specifying dependency, Spearman’s rank order correlations were run.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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,
Pit-1, Gi2, and GH genes
Evaluation of the expression of genes coding for
Gs, Pit-1, Gi2, and GH was performed on
the 24 somatotroph adenomas by Northern blot. The hybridization with
Pit-1 cDNA probe showed two transcripts, one major at 2.4 kb and one
minor at 4.5 kb. Quantitative analysis was performed on the major
transcript (16). As previously reported (24, 25), the transcripts of
Gs and Gi2 were detected in all tumors at
about 1.9 and 2.3 kb, respectively. A variable expression of mRNAs
corresponding to these genes was found. An example is shown in Fig. 1 for 16 somatotroph adenomas, grouped
according to the presence or absence of the gsp mutation.
With reference to S26 mRNA, Gs mRNA levels were
significantly lower in the gsp+ tumors than in the
gsp- tumors (P < 0.01; Figs. 1 and 2). Some gsp- adenomas
(tumors A9, A16, A17, and A18) contained very high amounts of
Gs mRNA. The levels of Gi2 and Pit-1
mRNAs were not significantly different in the groups (Fig. 2).
Expression of the GH gene was high and variable, but related neither to
the presence of the gsp oncogene (P > 0.5)
nor to the in vivo and in vitro GH secretion
(data not shown).
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,
Gi2, and Pit-1 genes
A positive correlation was found between the levels of the mRNAs
for both Gs and Gi2 (r = 0.64;
P < 0.0023; Fig. 3A), on
the one hand, and the mRNAs for Gs and Pit-1 (r =
0.57; P < 0.0061; Fig. 3B), on the other hand. In the
same way, Gi2 mRNA levels were positively correlated to
those of Pit-1 mRNA (r = 0.7; P < 0.0008; Fig. 3C). No significant correlation was found between GH mRNA content and
all of the other examined messengers (data not shown). An example of
the Northern blot analysis is shown in Fig. 4 for 14 somatotroph adenomas classified
according to their Gs mRNA levels.
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, and Pit-1 genes
An in vivo acute octreotide test was performed before
any treatment in 17 of 24 acromegalic patients. The maximal percentage
of octreotide-induced inhibition of plasma GH levels varied from 0 to
-97% (Table 1). In 16 of 24 tumors available for cell culture
studies, the maximal inhibitory effects of octreotide
(10-8 mol/L for 24 h) on GH release varied from
-10% to -96% (Table 1). A positive correlation (r = 0.7;
P < 0.04) was observed when the in vivo and
the in vitro octreotide-induced inhibition of GH secretion
was analyzed. Northern blot analysis of SSTR2 was performed on 18
somatotroph adenomas (5 gsp+ and 13 gsp-)
classified according to their variable octreotide sensitivities (Fig. 5). The blot showed a transcript of about
2.3 kb. The quantity of SSTR2 mRNA reported to S26 mRNA appeared highly
variable. A significant correlation was found between the expression of
SSTR2 mRNA and the percentage of octreotide-induced GH inhibition
in vitro (n = 12; r = 0.67; P <
0.025; Fig. 6) as well as in
vivo (n = 15; r = 0.7 P < 0.007; data
not shown). SSTR2 mRNA was not significantly more expressed in the 5
gsp+ tumors than in the 13 gsp-
(P < 0.4). Moreover, among the tumors used for cell
culture studies, the SSTR2 mRNA level was not different between the
groups (P < 0.45) despite the fact that the in
vitro octreotide-induced inhibition of GH secretion was
significantly higher in the 5 gsp+ tumors (-63 ± 7%)
than in the 7 gsp- (-30 ± 9%; P <
0.028). In contrast to SSTR2 mRNAs, the expression of
Gi2 and Pit-1 did not appear to be correlated with
octreotide sensitivity either in vivo or in vitro
(data not shown). Nevertheless, a significant correlation was found
between the messengers of SSTR2 and Gi2 (r = 0.55;
P < 0.02) as well as those of SSTR2 and Pit-1 (r
= 0.6; P < 0.01; data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. This result is partially contradictory with one
study founded only on a semiquantitative immunocytochemical analysis of
the Gs protein (26). Another study, based on
semiquantitative RT-PCR, has shown that the level of Gs
mRNA was not different in the two groups; nevertheless, the same
researchers found a difference when Gs protein
content was considered (27, 28). Arginine 201 of the
Gs subunit is the target for cholera toxin.
The toxin mimics the gsp mutation, and in the
mammosomatotroph GH3 cell line, it decreases the expression
of both Gs protein and messenger (29). In the
S49 line, the stimulation of adenyl cyclase by forskolin induces a
decrease in both Gs mRNA and protein (30). The low level
of Gs mRNA in gsp+ somatotroph tumors
suggests the existence of a negative compensatory feedback exerted by
the mutated Gs protein on the expression of its own
mRNA. Another compensatory adaptation to the Gs mutation
has been recently described by Lania and co-workers (31). These
researchers showed an increased phopshodiesterase activity in
gsp+ tumors, which could at least in part counterbalance the
constitutive activation of the cAMP-dependent pathway. These two
phenomena, by preventing the functional alterations induced by
Gs mutated protein, may be responsible for the large
clinical phenotype overlapping observed when gsp+ and
gsp- tumors are compared (4, 5, 6, 8, 9). Another hypothesis
explaining the lack of clear-cut differences in the clinical phenotype
of these two categories of tumors is supported by the high expression
of Gs gene observed in some gsp- tumors.
Bertherat et al. (32) have already shown that in GH tumoral
cells, high levels of wild-type Gs protein may promote
cAMP response element (CRE)-binding protein phosphorylation. In the HEK
293 cell line derived from human embryonic kidney cells, overexpression
of the wild Gs protein or the expression of the mutated
protein are both able to induce activation of cAMP pathway (33).
Furthermore, in somatotroph adenomas, gsp oncogene induces a
variable degree of resistance to GHRH (7, 34); in fact, the increased
expression of Gs protein could have a stronger impact
than the mutation itself on the intensity of the response (26).
Tumorigenesis could therefore be induced by either gsp
mutation or Gs overexpression, both leading to
constitutive activation of the cAMP-dependent pathway.
Conversely, we have not found any difference between gsp+
and gsp- tumors concerning the messengers for
Gi2, Pit-1, and GH. Our data are different from those
obtained from murine pituitary GH3 or GC cell lines
transfected with mutant or wild Gs genes (10, 11, 32).
In these cells, the Gs mutated protein was able to
induce a stronger activation of the rat Pit-1 and GH promoter through
the two CRE sites (11, 32). However, concerning regulation of gene
expression, it must be pointed out that important differences exist
between rodents and humans; the human Pit-1 promoter does not contain
CRE and is also very weakly regulated by the cAMP pathway (35).
Concerning GH mRNA and gsp oncogene, a slight difference in
GH secretion was reported between gsp+ and gsp-
tumors in vivo (6) and in vitro (31). Moreover,
we did not find a correlation between the levels of GH secretion and GH
gene expression. The lack of correlation could be expected in pituitary
adenomas, as GH levels are the result of complex regulatory mechanisms
concerning secretory steps not directly related to the expression of
hormone mRNA. These mechanisms could be altered in adenomas, as in the
clinically silent somatotroph adenomas (36).
In a previous study, Greenman et al. (37) showed that two
patients expressing SSTR2 mRNA have a good in vivo
octreotide response. Our results show a clear correlation between the
sensitivity in vivo and in vitro to octreotide
and the expression level of the SSTR2 subtype. Our finding are in
agreement with studies showing a diminished binding of both radioactive
SRIF and octreotide in resistant adenomas (38, 39). As is the case for
the gsp mutation (6), assessment of the expression of SSTR2
gene could also be considered a clue to the capacity of the tumor to
respond to the somatostatin analog. Despite a better octreotide
sensitivity of gsp+ adenomas, SSTR2 mRNA was not different
in the two categories of tumors. This fact suggests that the
gsp oncogene does not proceed through the increase in SSTR2
gene expression to improve the sensitivity. SSTR5 is probably also
important in regulating GH secretion by somatostatin agonist (40). It
would be interesting to compare SSTR5 mRNA expression between
gsp+ and gsp- tumors. Postreceptor alterations
could also be implicated in the loss of sensitivity, as was suggested
by Bertherat et al. (41). In the S49 cell line, activation
of cAMP triggered by the ß-adrenergic agonists leads to enhancement
of the somatostatin inhibition due to the increment in both
Gi2 protein and mRNA (30). However, we have not found
any correlation between the expression of postreceptor factors, such as
Gi2 and Pit-1 genes, and the sensitivity to the
octreotide in somatotroph adenomas. The difficulties of assessing how
these factors modify sensibility come from the fact that somatostatin
agonists activate more than one SSTR isoform to run more than one
transduction pathway.
The expression of Gi2 and Pit-1 genes was positively
correlated with those of SSTR2. Moreover, correlations were found
between the expression of Gi2, Pit-1, and
Gs genes. Some of these correlations have been
previously shown in the S49 cell line (30). In human somatotroph
adenomas, Hamacher and co-workers (26) found a correlation between the
proteins Gs and Gi2. Transfected in the
GH3 cell line, Gs is able to
stimulate expression of the Pit-1 gene (11, 32). The correlations found
between the expression of these genes, all coding for proteins
implicated in the processes of differentiation and secretion of
somatotroph cells, strongly suggest a concerted genic dysregulation,
which could lead to the phenotypical dedifferentiation present in these
tumors.
It is most likely that pituitary tumorigenesis takes place in two
steps, initiation and promotion (42). The gsp oncogene could
be considered an initiating factor. However, cells bearing the
gsp oncogene are able to develop some mechanisms to
counteract the disturbances induced by the Gs mutation,
thus restricting its phenotypical impact. The coordinated loss of
expression of certain genes may activate the process of tumoral
promotion. The diminished sensitivity to octreotide may represent one
step in the dedifferentiation drift, as an altered response results at
least in part from the impaired expression of SSTR2 mRNA. However,
improvement of the sensitivity associated with the gsp
oncogene seems to proceed in a way different from SSTR2 expression.
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Footnotes |
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Received February 24, 1999.
Revised May 7, 1999.
Accepted May 13, 1999.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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P. Jaquet, A. Saveanu, G. Gunz, F. Fina, A. J. Zamora, M. Grino, M. D. Culler, J. P. Moreau, A. Enjalbert, and L'H. Ouafik Human Somatostatin Receptor Subtypes in Acromegaly: Distinct Patterns of Messenger Ribonucleic Acid Expression and Hormone Suppression Identify Different Tumoral Phenotypes J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 781 - 792. [Abstract] [Full Text]
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) somatotroph adenomas. The
quantification of Gs
