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Original Studies |
Laboratoire d’Explorations Fonctionnelles Endocriniennes and INSERM U515 (N.B., V.G., A.L., Y.L.B., C.G.), Hôpital Trousseau; and Clinique des Maladies Endocriniennes et Métaboliques (X.B.), Hôpital Cochin, AP-HP PARIS, France
Address correspondence and requests for reprints to: Dr. Christine Gicquel, Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, 26 Avenue Arnold Netter, 75012 Paris, France. E-mail: christine.gicquel{at}trs.ap-hop-paris.fr
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Abstract |
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We hypothesized that maternal LOH in malignant adrenocortical tumors could be responsible for loss of p57KIP2 gene expression and, thus, could favor progression through the cell cycle.
We investigated 3 normal adrenals, 31 adrenocortical tumors [11 tumors with normal expression of the IGF-II gene (mainly benign) and 20 with IGF-II gene overexpression (mainly malignant)], and the human adrenocortical tumor cell line NCI H295R for expression of the p57KIP2 gene, G1 cyclins (cyclin D2 and E) and G1 CDK (CDK2, CDK3 and CDK4) protein contents and for kinase activity of G1 cyclin-CDK complexes.
The expression of p57KIP2, G1 cyclins, and G1 CDKs in benign tumors was similar to that in normal adrenal tissues, as were kinase activities of G1 cyclin-CDK complexes. By contrast, abrogation of the p57KIP2 gene expression and increased expression of G1 cyclins (cyclin E) and G1 CDKs (CDK2 and CDK4) were associated with high activity of G1 cyclin-CDK complexes in malignant tumors and in the H295R cell line.
These data suggest that the p57KIP2 gene might act as a tumor suppressor gene in adrenocortical tumors. Maternal LOH with duplication of the paternal allele or pathological functional imprinting of the 11p15 region are responsible for loss of expression of the p57KIP2 gene and increased expression of the IGF-II gene. Consequently, both events favor cell proliferation in malignant adrenocortical tumors.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The 11p15 region also includes other growth-related imprinted genes (H19, p57KIP2, KvLQT1, TSSC3, TSSC5), most of them expressed from the maternal allele and with antiproliferative functions (review in Ref. 4). Among them, p57KIP2, 700 kb centromeric to the H19/IGF-II locus (5, 6), is paternally imprinted and expressed from the maternal allele (7, 8). It encodes a cyclin-dependent kinase (CDK) inhibitor (CKI) from the CIP/KIP family. CKIs bind to cyclin-CDK complexes and inactivate their catalytic domains, thereby negatively controlling cell cycle progression (9). Indeed, overexpression of p57KIP2 leads to G1 cell cycle arrest (5, 6). This gene is particularly expressed in adrenal tissues (10, 11). Because it maps to the 11p15 region, is expressed from the maternal allele, and is a CKI, the p57KIP2 gene is, thus, an excellent tumor suppressor gene candidate for adrenocortical tumorigenesis.
Transgenic mice that no longer carry the p57KIP2 gene exhibit adrenal hyperplasia and some phenotypes from the Beckwith-Wiedemann syndrome (BWS), a disorder characterized by overgrowth and predisposition to cancer (11). Heterozygous mutations in the p57KIP2 gene have been reported in 5% of patients with BWS (12, 13, 14, 15), but no somatic mutations have been described in tumors, particularly in Wilms’ tumors (15, 16, 17). Conflicting results have been reported about the expression of p57KIP2 in Wilms’ tumors. Some studies showed reduced expression (12, 18, 19), whereas others reported normal expression of the p57KIP2 gene (17, 20). The expression of the p57KIP2 gene in adrenocortical tumors has not been extensively studied and was recently reported to be abrogated in malignant tumors (10).
The aim of the present work was to assess the involvement of p57KIP2 in adrenocortical tumorigenesis. We examined the expression of the p57KIP2 gene, G1 cyclins, and G1 CDKs in adrenocortical tumors. We showed that p57KIP2 expression was abrogated in most tumors with IGF-II gene overexpression and imprinting mistakes (mainly malignant tumors). G1 cyclins and G1 CDKs expression (particularly cyclin E and CDK2) was also highly increased in these tumors overexpressing the IGF-II gene. By measuring the kinase activity of G1 cyclin-CDK complexes, we found that most tumors with increased cyclin and CDK contents and decreased p57KIP2 expression have high CDK2-associated kinase activities.
These data suggest that loss of function of the p57KIP2 gene participates to overactivity of G1/S phase cyclin-CDK complexes in adrenocortical tumors and likely contributes, in association with overexpression of the IGF-II gene, to tumor proliferation.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Thirty-one adult patients, 17–80-yr-old (3 males and 28 females) with sporadic adrenocortical tumors, were included in the study. None of them had features of any tumor-predisposing syndrome (BWS, McCune-Albright syndrome, Multiple Endocrine Neoplasia type 1 syndrome, or Li-Fraumeni syndrome).
Hormonal status and the stage of the tumor as either localized, regional, or metastatic were evaluated as described previously (21). Tumors were defined as benign, suspect, or malignant according to histological features (1), and two groups of tumors were distinguished on the basis of IGF-II messenger RNA (mRNA) expression and abnormalities of the 11p15 region.
Group 1 consists of 11 tumors without overexpression of the IGF-II gene or 11p15 LOH. The patients were diagnosed as having localized adrenocortical tumors (weight, 11–31 g), 10 of them with a strictly benign histological appearance.
Group 2 consists of 20 tumors with overexpression of the IGF-II gene and abnormalities of the 11p15 region. Four tumors were considered as suspect (weight, 28–54 g), and 16 were initially diagnosed as adrenocortical carcinomas (weight, 69–3600 g).
Most tumors were hormonally active. Clinical, pathological, hormonal,
and molecular data are summarized in Table 1
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). Tissue fragments, obtained at surgery, were immediately frozen in liquid nitrogen and stored at -80 C until protein and RNA extraction could be performed.
NCIH295R cell line
The human steroid-producing adrenocortical tumor NCIH295R cell line, which is derived from a malignant tumor, was also studied (kindly provided by W. Rainey, University of Texas, Dallas, TX) (22).
Methods
RNA isolation and Northern blot analysis of p57KIP2 mRNA.Total RNA was extracted by the CsCl/guanidine isothiocyanate method (23). Total RNA (10 µg) was loaded onto a 1.2% agarose/2.2 M formaldehyde gel, submitted to electrophoresis, and transferred to Hybond C membrane (Amersham Pharmacia Biotech, Uppsala, Sweden). Normal control adrenal RNA was obtained from glands surgically removed during large nephrectomy for kidney cancer. Placental RNA, which is a rich source of p57KIP2 mRNA, was used as a positive control. The blots were prehybridized and hybridized to 32P-labeled probes, washed, and exposed to film, as described previously (24).
A cDNA probe of 279 bp corresponding to the nucleotides 1238–1516 of the human p57KIP2 gene (GenBank accession no. U22398) was amplified by PCR. Sense and antisense primers were, respectively, 5'-CGTCCCTCCGCAGCACATCC and 5'-CCTGCACCGTCTCGCGGTAG. Quantification: hybridization signals were measured by densitometric analysis using a GS700 imaging densitometer and the molecular analyst data system (Bio-Rad Laboratories, Inc., Richmond, CA). The intensity of the bands was compared with the 28S RNA band intensity and expressed in arbitrary units (AUs).
Protein analysis
Protein extraction.
Frozen tissues (average weight, 100 mg)
were quickly homogenized on ice using a Polytron homogenizer in 3 mL
lysis buffer [50 mM Hepes (pH 7), 250 mM NaCl,
1 mM sodium orthovanadate, 2 mM sodium
pyrophosphate, 0.1% Nonidet P-40, and 1 mM
dithiothreitol] containing protease inhibitors (5 mM
EDTA, 1 mM PMSF, 1 µg/mL leupeptin, and 1 µg/mL
aprotinin). The homogenates were incubated for 1 h at 0 C and
centrifuged at 13,000 rpm for 30 min at 4 C. The
supernatant was collected and frozen at -20 C. Aliquots of supernatant
were collected for protein determination by the Bradford method
(Bio-Rad Laboratories, Inc. protein assay; Bio-Rad Laboratories, Inc.).
Western immunoblotting.
Protein extract (150 µg) was
submitted to SDS-10% PAGE under reducing conditions (10%
ß-mercaptoethanol). Proteins were transferred to 0.45 µm
nitrocellulose membranes (BA 85; Schleicher & Schuell, Inc., Dassel, Germany) for 90 min at 130V. Membranes were
blocked 2 h at room temperature in phosphate-buffered saline (PBS)
1x pH 7.4 (0.14 M NaCl, 3 mM KCl, 8
mM Na2HPO4, and 15 mM
KH2PO4) containing 0.2% Tween (T) and 10%
powdered milk. This was followed by incubation with diluted antiserum
(final concentration, 0.2 µg/mL) in 5% milk-PBS for 20 h at 4
C. All antisera (anti-cyclin D2, anti-cyclin E, anti-CDK2, anti-CDK3,
anti-CDK4, anti-proliferating cell nuclear antigen (PCNA),
anti-p27KIP1, and anti-p21CIP1) were purchased
from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).
The membranes were then washed three times in PBS-T buffer and incubated for 1 h at 37 C with horseradish peroxidase-conjugated goat antirabbit IgG (Amersham Pharmacia Biotech), diluted in milk-PBS. The membranes were then washed three times in PBS-T, after which they were incubated for 1 min at room temperature in chemiluminescence reaction detection reagents (ECL Western blotting; Amersham Pharmacia Biotech). The blots were then exposed to x-ray films, and signal intensity was measured by scanning densitometry and expressed in AUs.
To allow comparisons between different experiments, the same placental protein extract was used for each gel.
Immunoprecipitation and protein kinase assays.
Protein
extracts (60 µg) were incubated at 4 C overnight with anti-CDK2 or
anti-CDK4 (0.4 µg) antibodies. Cyclin-CDK complexes were then
isolated by incubation at 4 C for 1 h with 50 µl protein
A-Sepharose beads 6MB (Amersham Pharmacia Biotech). The beads were then
washed twice with lysis buffer and once with kinase buffer [50
mM Tris HCl (pH 7.4), 10 mM MgCl2, and 1
mM dithiothreitol] and incubated for 30 min at 30 C in 25
µl kinase buffer in the presence of either 5 µg histone H1
(Roche Molecular Biochemicals, Mannheim, Germany)
or 1 µg GST-pRb corresponding to amino acids 769–921 mapping within
the carboxy-terminal domain of pRb of mouse origin (Santa Cruz Biotechnology, Inc.), 1 µCi of 
32P ATP (3000
µCi/mmol), and 50 µM ATP. Reactions were stopped by
adding 40 µl 2x SDS sample buffer [62.5 mM Tris HCl (pH
6.8), 2% SDS, 10% glycerol, 0.025% bromophenol blue, and 5%
ß-mercaptoethanol]. The samples were then boiled for 5 min and
analyzed by 7.5% SDS-PAGE. 32P-labeled proteins were
detected by autoradiography, and signal intensity was measured by
scanning densitometry and expressed in AUs.
Statistical analysis.
All analyses were performed using the
statistical package Statview (Abacus Concepts, Inc., Berkeley, CA).
Medians were compared by the nonparametric Mann-Whitney test, and
results are expressed as median (minimum to maximum). Coefficients of
correlation were evaluated using linear regression. A P
value less than 0.01 was regarded as significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In normal adult adrenals, p57KIP2 mRNA
was readily detectable in Northern blots with a major transcript of 1.7
kb (Fig. 1A). In tumors from group 1
(tumors without abnormalities of the 11p15 region and with normal
expression of the IGF-II gene, mainly benign tumors),
p57KIP2 gene expression was always detectable
[116 AU (12–311)]. By contrast, most tumors from group 2 (with high
IGF-II gene expression and imprinting mistakes, mainly malignant
tumors) had no or low amounts of p57KIP2 mRNA
content when compared with tumors from group 1 (0 AU (0–186),
P = 0.0001). Indeed, as shown in Fig. 1, A and B, and
Table 2, p57KIP2
mRNA was undetectable in 14 of 19 tumors from group 2. In the remaining
five tumors, p57KIP2 mRNA was detectable: four of
these latter tumors had, at least, partly conserved the maternal 11p15
allele (tumors from patients 35, 47, 55, and 100; Table 1).
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G1 cyclin and CDK protein contents in adrenocortical tumors
Cyclins D2 and E, and CDKs 2, 3, and 4 protein expression levels
were evaluated by immunoblotting using specific antibodies. Tumors from
group 1 had cyclins D2 and E and CDK2 and CDK4 levels in the same range
as normal adrenal tissues (Fig. 2 and
Table 2). By contrast, most tumors from group 2 and the NCI H295R cell
line had significantly higher levels in cyclin E (P =
0.0001), CDK2 (P = 0.0001), and CDK4 (P
= 0.005) than tumors from group 1 (Fig. 2 and Table 2). The level of
cyclin D2 protein was not significantly different between the two
groups of tumors. Furthermore, CDK3 protein was undetectable in most
adrenal samples. Individual and median values of cyclin and CDK protein
levels are summarized in Fig. 2 and Table 2.
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To determine whether the difference in the amounts of G1 cyclins
and their CDK partners and of p57KIP2 mRNA
contents were associated with changes in levels of protein kinase
activity, we performed in vitro kinase assays. The
cyclin-CDK2 complexes were immunoprecipitated with anti-CDK2 antibodies
and assayed for their kinase activities toward histone H1: tumors from
group 1 generated levels of kinase activity in the same range as normal
adrenal tissues (Fig. 3, A and B, and
Table 2). By contrast, the median kinase activity was much higher in
tumors from group 2 [448 AUs (10–1641)] than in tumors from group 1
[47 AUs (13–153), P = 0.003]. Some tumors from group
2, however, had CDK2-associated histone kinase activity in the range of
normal adrenal tissues despite high cyclin and CDK protein contents
(Table 2). Some of these tumors were tumors with abrogation of
p57KIP2 gene expression (Fig. 3C). Eight of the
20 patients from group 2 received mitotane therapy before surgery
(Table 1). None of these tumors exhibited high CDK2-associated histone
kinase activity, and the question of deleterious effects of mitotane on
kinase activities could be raised.
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and Table 2).
Proliferative activity was measured by PCNA expression. PCNA
protein contents were significantly higher in tumors from group 2 than
tumors from group 1 (P = 0.0003) (Table 2) and
correlated with CDK2- (r2 = 0.39,
P = 0.0002) and CDK4- (r2 = 0.36,
P = 0.0005) kinase associated activities (Fig. 3E).
p21CIP1 and p27KIP1expression
The increased CDK2-associated histone kinase activities in
malignant tumors can be related to increased expression of G1 cyclins
and G1 CDK and/or decreased expression of CKIs. Abrogation of
p57KIP2 expression in malignant tumors can
account for enhanced CDK kinase activities. However, other CKIs from
the CIP/KIP family, such as p21CIP1 and
p27KIP1 are also involved in control of G1
cyclin-CDK complexes. Therefore, we examined the amounts of
p21CIP1 and p27KIP1 protein
in tumors and normal adrenals to investigate whether up-regulation of
p21CIP1 or p27KIP1 could
account for normal CDK2-associated histone kinase activities in some
malignant tumors with high cyclin and CDK contents. Analysis of
p21CIP1 showed that p21CIP1
expression was not detectable in two normal adrenals and in most tumors
(Fig. 4A). It was only detected in 2 of 8
tumors from group 1 and 3 of 14 tumors from group 2.
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, A and B, and
Table 2), but did not correlate negatively with CDK2-associated histone
kinase activities (Fig. 4C). |
Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In the current study, we examined the expression of the p57KIP2 gene in addition to the expression of G1 cyclins, G1 CDKs, and their corresponding kinase activities. We report here that p57KIP2 expression was abrogated in most tumors exhibiting 11p15 LOH or 11p15 pathological imprinting (tumors from group 2). This is consistent with the fact that, in both cases, the 11p15 region has acquired a paternal epigenotype. The p57KIP2 expression was maintained in tumors from group 1 (mainly benign tumors). These data agree with the study of Liu et al. (10), showing that p57KIP2 expression was abrogated in adrenocortical tumors overexpressing IGF-II.
Analysis of G1 cyclins and G1 CDKs protein levels by immunoblotting showed that tumors from group 2 had significantly more cyclin E, CDK2, and, to a lesser extent, CDK4 than tumors from group 1 or normal adrenals. This is the first study to analyze cell cycle components in adrenocortical tumors. In the present work, high G1 cyclins and G1 CDKs contents appeared to be associated with the malignant phenotype and did not depend on tumor extension because levels were similar in localized and metastasized carcinomas. In breast cancer, cyclin E overexpression has been shown to be associated with decreased survival and, thus, to be an independent prognostic marker (28). The prognostic value of these parameters in adrenocortical tumors remains to be evaluated. The mechanism for high cyclin and CDK expression in tumors from group 2 remains unclear. CKIs have not been shown to control the expression of cyclins or CDKs. A candidate regulatory gene might be IGF-II, which is overexpressed in tumors from group 2. The precise function of the IGF system in control of the cell cycle is not well documented, but it has been shown that IGF-I could be involved in the control of cyclin D1 expression (in a human osteosarcoma cell line) (29) and that the type 1 IGF receptor participates in the regulation of cdc2 mRNA levels in fibroblasts (30). We hypothesize that IGF-II could control the expression of G1 cell cycle components, and additional studies should focus on this. If true, a positive control by IGF-II of G1 cyclins and G1 CDKs (particularly cyclin E and CDK2) expression would amplify the deleterious consequences of loss of p57KIP2 expression in tumor proliferation.
By comparing kinase activities of G1 cyclin-CDK complexes, we found that the activities of tumors from group 1 were similar to that in normal adrenals. By contrast, immunoprecipitated CDK2-cyclin complexes isolated from tumors from group 2 highly phosphorylated histone H1 proteins. Most of these tumor samples also exhibited low or absent p57KIP2 expression. However, some tumors from group 2 had kinase activities in the same range as normal adrenals despite high G1 cyclin and G1 CDK contents and low p57KIP2 expression. We, thus, examined the expression of two other CKIs from the KIP family, p21CIP1 and p27KIP1, which also regulate progression from G1 into S phase of the cell cycle. P21CIP1 was detectable in only a few tumors. P27KIP1 protein contents seemed to be higher in tumors from group 2 than in tumors from group 1 or normal adrenal tissues, but was not up-regulated in the malignant tumors with low CDK2-associated histone kinase activities. The reason for low kinase activities in these malignant tumors with high cyclin and CDK contents and low p57KIP2 remains unexplained. The observation that most of the tumors with low CDK2-associated histone kinase activity were tumors from patients previously treated with mitotane suggests that mitotane might affect CDK activity.
In conclusion, we have shown that in malignant adrenocortical tumors, major cell cycle control proteins as p57KIP2 and G1 cyclin-CDK complexes are deregulated. These changes are associated with an overactivity of G1/S phase cyclin-CDK kinases, consistent with an important role for p57KIP2 in tumorigenesis. The mechanism of overexpression of CDK2, CDK4, and cyclin E remains unclear, and additional study would be necessary to understand the precise role of IGF-II and type 1 IGF receptor in control of G1 cyclin and G1 CDK expression.
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Footnotes |
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Received July 19, 1999.
Revised September 9, 1999.
Accepted September 14, 1999.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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