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Departments of Scienze Biomediche [B. S., D. P., A. S., A C.], di Medicina Interna [C. C., M. B.], and Scienze Igienistiche, Microbiologiche e Biostatistiche [T. A.], Università di Modena e Reggio Emilia, 287-41100 Modena, Italy
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Introduction |
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ODC (EC 4.1.1.17), the first and rate-limiting enzyme of polyamine biosynthesis, was shown to be critical in cell transformation and suggested to be a proto-oncogene (3) . ODC activity is regulated by a unique protein, OAZ, that, after being induced by high levels of intracellular polyamines, binds and inhibits ODC, accelerating its degradation by the 26S proteasome system; OAZ also inhibits polyamine uptake from the extracellular compartment and may accelerate polyamine release from the cells (4) . The second enzyme of polyamine biosynthesis, also a rate-limiting one, is AdoMetDC (EC 4.1.1.50), required for the production of SPD and SPM from putrescine and adenosylmethionine. A catabolic pathway (retroconversion pathway), which is regulated by SSAT (EC 2.3.1.57), leads to polyamine degradation or excretion (5) . SSAT is induced by polyamine overaccumulation, thus taking part, together with OAZ, in the mechanisms that control intracellular homeostasis of these amines. Very recently, we have shown that expression of the genes coding for ODC, OAZ, AdoMetDC, and SSAT is cell cycle related in human dermal fibroblasts, leading to coordinate variations in the intracellular concentrations of polyamines, with cyclical phases of depletion and accumulation during cell cycle progression (6) .
Clusterin (also named SGP-2 and many other acronyms) is a heterodimeric glycoprotein present in most animal tissues and body fluids (7) . It is overexpressed in the regressing rat prostate 2–10 days after androgen ablation (8) . In general, expression of clusterin is down-regulated during cell proliferation (9) but up-regulated under conditions inducing cell suffering, cell atrophy, or organ involution (7 , 8) , in recent data from our laboratory, is induced in quiescent cells (10) . Clusterin expression thus shows an inverse pattern to that of ODC in prostate. A role in the process of inhibition of apoptosis and induction of cell survival has been proposed for this gene (11) , which may bear some relationship with the selection of the transformed phenotype and acquisition of hormone independence.
Given the complexity of the regulation of polyamine metabolism, we set out to overcome the limitations of previous studies by measuring the expression levels of the entire set of genes that regulate polyamine metabolism. The levels of their mRNAs were measured in benign and malignant areas, dissected from the same radical prostatectomy specimens, together with clusterin, the expression patterns of which have been studied extensively in our laboratory (8, 9, 10) , histone H3, a marker of cell proliferation, the mRNA of which accumulates in S phase of the cell cycle (12) , and Gas1, involved in growth suppression and maintenance of the quiescent state (13) . Finally, for comparison, the levels of the mRNA coding for GAPDH, a typical house-keeping gene, was also detected in the same specimens.
The data allowed a comparison, not only of the levels of the single transcripts in normal and tumorous tissues of different grade of prostatic malignancy but also between the patterns of expression of the whole set of genes, revealing the characteristic expression profiles that may establish during neoplastic transformation. Furthermore, by appropriate statistical analysis, we have shown significant correlations between expression levels of the genes studied, which may help to understand their involvement in CaP progression, and provide molecular markers of malignancy that may complement those in current clinical use.
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Materials and Methods |
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Patient Samples.
Radical prostatectomy samples were obtained from 23 patients with
tumors graded from Gleason grades 1 to 5 (Gleason scores 2 to 9).
Immediately after total prostatectomy, a specimen of about 0.5
cm3 in size was excised out from the cancerous
portion of each individual gland. A second well separated area
of benign (normal) tissue was also dissected. Both specimens were
quickly frozen on a flat glass surface at -80°C, covered with dry
ice powder, to preserve the tissue orientation and to generate a
suitable cutting surface for the cryostat. Starting from the top
surface, alternate 14-µm sections and tissue slices of about 200 mg
were made from both the cancerous and normal specimens. The 14-µm
tissue sections were stained and used for the histopathological and
morphological characterization of the thick tissue slice between the
two 14-µm sections. Two thick slices were obtained from each
specimen. Only normal specimens with no sign of benign prostatic
hypertrophy or tumor invasion and a similar relative epithelial cell
and stromal content to that of the cancerous counterparts were used as
controls. One of the two 200 mg slices from each specimens (normal or
cancerous) was used for total RNA extraction; the other one was used
for Western blot analysis and enzyme assays.
Northern Hybridization Analysis.
Total RNA was extracted from frozen human tissue specimens using
RNAfast (Molecular Systems, San Diego, CA). Ten-µg aliquots were then
electrophoresed on a 1% agarose-formaldehyde gel, blotted onto
Hybond-N nylon membranes (Amersham Italia S.r.l.), and then hybridized
to the specific cDNA probes. The specific cDNA probes were previously
purified and labeled by random priming
[32P]dCTP incorporation as described previously
(14)
. The Gas1 cDNA, kindly donated by Dr G. Del
Sal (C. I. B. Consorzio Interuniversitario Biotecnologie,
Trieste, Italy) (13)
, and the histone H3 probe, kindly
donated by Dr G. Stein (Department of Biochemistry and Molecular
Biology, University of Florida College of Medicine, Gainesville, FL)
(15)
, were purified, labeled, and used following the same
procedures. Quantitation of the autoradiograms was obtained by
densitometric scanning using a LKB Ultrascan XL densitometer.
Statistical Analysis.
The statistical significance of the differences between the mean values
of the abundance of each mRNA, in the normal and cancerous portions of
the prostate gland, was determined by paired comparison t
test analysis (two-tailed). The same analysis was applied to assess the
statistical significance of the above differences, between normal and
cancerous portions, after grouping the data as a function of the
differentiation grade, tumor localization, prognosis, and total PSA
level at diagnosis. The Pearson r test analysis (two-tailed)
was used to assess significant correlations (positive or negative)
between the values expressing the mRNA levels of each gene, determined
either in normal or cancerous tissues. The logistic regression
analysis was used for the classification of the tumors as a function of
the levels of expression of group of genes in the cancerous part of the
prostate. This was compared with the classification based on the
differentiation grade or tumor localization.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Fig. 1A
shows a representative Northern blot in which the
expression levels of H3 and Gas1 mRNAs are inversely related in matched
cancerous and normal specimens. For example, in the Gleason score 2
tumor, Gas1 was up-regulated but H3 was
down-regulated, suggesting that, in less aggressive CaPs, overall cell
proliferation is probably lower than in the normal tissue. The opposite
was true in the Gleason scores 5 (Gleason grade: 3+2) and 8 (Gleason
grade: 5+3) tumors, where Gas1 was down-regulated, whereas
H3 was overexpressed with respect to normal tissue.
These data are consistent with the positive correlation between CaP
progression and proliferation activity that was shown previously with
Ki-67/MIB1 or PCNA/cyclin as specific markers of cell proliferation
(16, 17, 18)
.
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. In the less aggressive tumor,
with lower proliferative activity (Gleason score 2), ODC is
up-regulated, and this is accompanied and perhaps compensated by the
increase in OAZ mRNA. The AdoMetDC transcript is not induced, and a
minor increase of the mature SSAT mRNA form (1.3–1.5 kb) is evident,
probably leading to a slight increase in polyamine degradation and
excretion. This pattern, exhibited by a well-differentiated cancer, is
consistent with the hypothesis that ODC induction, which should be
balanced by activation of the regulatory steps of the polyamine
metabolism to prevent detrimental over accumulation of these
polycations, is an early event during cell transformation
(1)
. In contrast, in the actively proliferating Gleason
score 8 CaP (Fig. 1B)
, the induction of ODC does not seem to
be counterbalanced by OAZ overexpression. Equally, the
levels of the AdoMetDC transcript are dramatically higher in this
specimen, and the increased accumulation of higher polyamines (SPD and
SPM), which inevitably would follow the induction of the two
biosynthetic enzymes, may be partly balanced by SSAT
overexpression. This would result in intracellular polyamine
concentrations capable of supporting a high rate of cell proliferation
without jeopardizing cell survival.
Clusterin (SGP-2) is down-regulated both in Gleason scores 2
and 8 CaP specimens (Fig. 1B)
, showing that changes in the
expression of this gene are both the inverse of ODC and are
among the earliest events of prostate tumor development.
The densitometric values obtained from autoradiograms of Northern
hybridization experiments performed in all normal and cancerous
specimens (n = 23) were then analyzed by
t test[p.c.], a paired comparison
t test. Although not all of the mRNAs could be titrated in
all of the specimens studied, the number of determinations varied
between 18 (for H3) to 23 (for OAZ). The mean values for the abundance
of each transcript, in normal and cancerous portions of the same gland,
were calculated and are shown in Fig. 2
. The mRNA levels of each of the regulatory proteins of polyamine
metabolism were significantly higher in the tumor than in the normal
portion of the gland (ODC: t = -2.852,
n = 20, P = 0.008;
OAZ: t = 2.220, n = 23, P = 0.038; AdoMetDC:
t = 2.462, n = 21,
P = 0.023; SSAT: t = 2.767, n = 22, P = 0.009), confirming a very recent report showing that ODC
activity and protein are significantly higher in human CaP as compared
with paired benign tissue (19)
. Conversely, the level of
clusterin transcript in CaP specimens was significantly lower than in
normal tissue (t = -2.719;
n = 20; P = 0.009).
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A trend toward higher histone H3 mRNA levels, in 61% (11/18) of the patients, and lower Gas 1 mRNA levels, in 68% (15/22) of the patients, in CaP tissue compared with the matched normal tissue was also detected. The differences approached but did not reach statistical significance (H3: t = -1.948; n = 18; P = 0.068; Gas1: t=1.104; n = 22; P = 0.540). Taken together, these data suggest that in CaPs, more cells are proliferating and fewer are quiescent, which is further supported by the decrease in SGP-2 expression that we have shown previously to occur after application of a proliferation stimulus (9 , 10) . Higher levels of GAPDH mRNA detected in cancer with respect to the normal portion of the gland were not significant (t = 1.314; n = 22; P = 0.203), as in only 55% of the patients (12 of 22) was GAPDH expression higher in cancerous than in normal tissue.
The mean values of the mRNA accumulation in CaPs were next analyzed as
a function of the differentiation grade (Gleason grade 1–2, well
differentiated; grade 3, moderately differentiated; grade 4–5, poorly
differentiated). In poorly differentiated cancers, the levels of ODC,
AdoMetDC, SSAT, Gas1, and SGP-2 transcripts, expressed as percentages
of the mean values determined in the normal counterparts (Fig. 3A)
, exhibited the largest significant differences
(t test[p.c.]). In moderately
differentiated tumors, only ODC was significantly
overexpressed, whereas H3 mRNA reached its highest level, not far from
statistical significance (t = -2.378;
n = 6; P = 0.063).
Paradoxically, in the well-differentiated cancers, the expression
profile for H3 and Gas1 appeared to be opposite
of that observed in poorly differentiated tumors: i.e., H3
mRNA accumulation was lower and Gas1 mRNA accumulation was higher in
the cancerous portion of the gland. However, this did not reach
statistical significance (t
test[p.c.]). This was consistent with the data
shown previously in Fig. 1B
.
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, the up-regulation of
ODC and AdoMetDC and the down-regulation of
Gas1 and SGP-2 were all statistically
significant. H3 overexpression reached statistical
significance in organ confined tumors, where also ODC and SSAT mRNAs
levels were significantly higher than controls.
In patients with negative prognosis (i.e., with at least one
of the following features: regular increases of total PSA after
surgery; lymph node involvement; presence of distant metastasis; Fig. 3C
), ODC, AdoMetDC, and
SSAT were significantly up-regulated, and Gas1
and SGP-2 were significantly down-regulated. However,
SSAT was significantly overexpressed in patients with
favorable prognosis as well.
When the data were analyzed as a function of total PSA levels at
diagnosis (Fig. 3D)
, significant differences between
cancerous and normal tissue levels of ODC, SSAT, H3, and SGP-2
transcripts were observed in patients with the highest total PSA levels
(>10 ng/ml), whereas ODC was significantly overexpressed, even in
patients with total PSA in the range of 0.1–4.0 ng/ml. Total PSA
values are related mainly to tumor volume and to the disruption of the
barriers between the site of PSA production and the capillary bed
(20)
. The concurrent increase in the number of cells in S
phase (as indicated by histone H3 and ODC mRNAs overexpression) and
total PSA levels may be related to a higher growth rate and
invasiveness of CaP.
Independently of the classification system used for CaP specimens,
tumor levels of SGP-2 mRNA were 
50% lower compared with the normal
counterpart. This was even observed in well-differentiated tumors, thus
representing an early event during CaP progression that may result,
among other molecular mechanisms, from a specific genetic loss. The
clusterin gene is present as a single copy and maps to human
chromosome 8 (21)
in the 8p21 region (22)
. It
has been hypothesized that one (or more) tumor suppressor genes are
located on human chromosome 8, which contains one of the most
frequently deleted loci observed in prostate cancer cells, 8p22–8p21
(23)
. Furthermore, when Dunning rat prostate carcinoma
cells were used as recipients for human chromosomes, metastasis
suppressor activities were also identified on chromosome 8
(24)
. The role played by potential deletion of the
clusterin locus in the expression levels of SGP-2 is
currently under investigation in our laboratory.
Statistically significant correlations between the levels of the
transcripts within the same CaP specimens, grouped as shown in Table 1
, were sought by applying the Pearson r test. Of the 28
possible correlations, 4 were found in the normal portions of the gland
and three in the cancerous portions (Table 1A)
. When the specimens were
grouped according to the differentiation grade (Table 1B)
, local
invasiveness (Table 1C)
, and prognosis (Table 1D)
, the number of
significant correlations was always lower with higher malignancy. This
picture suggests that specific biochemical lesions, consisting of the
progressive loss in the coordinate levels of expression of the genes
studied, are major events in the metabolic derangement that accompanies
neoplastic transformation.
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confirms the positive correlation between
ODC/SSAT levels in normal tissue. Thus, enhancements of ODC activity
and consequent increases in polyamine concentrations are usually
followed by induction of SSAT, which contributes to maintenance of
intracellular polyamine homeostasis. The observed overexpression of ODC
mRNA in early S-phase cells and the elevation of SSAT mRNA in late S
and G2-M phases (6)
support this
correlation. The positive correlation between H3/SSAT mRNA levels can
also be reconciled, because H3 mRNA levels peak in S phase. Also,
although the ODC/SSAT correlation is statistically significant in less
malignant tumors (Table 1C
and 1D)
, it is lost in more advanced
cancers (Table 1B
1C
1D)
. Therefore one of the mechanisms that prevents
polyamine overaccumulation is lost with increasing tumor grade and loss
of differentiation.
OAZ and SSAT mRNA levels were significantly correlated not only in the
CaP specimens taken together (Table 1A)
but also in all three groups of
advanced cancers (Table 1B
1C
1D)
. This implies that changes in the
expression of these two genes, which are essential for the regulation
of intracellular polyamine homeostasis, occur in a coordinate manner
even after neoplastic conversion. It is likely that the increased
expression of OAZ and SSAT in cancer cells
prevents polyamine concentration to reach levels that would be toxic to
the cell.
Interestingly, in the normal tissue contiguous to a poorly differentiated prostate cancer, a significant negative correlation (t = -0.746; n = 8; P = 0.034) between the decrease in ODC and increased clusterin gene expression was observed (compared with the adjacent tumor tissue). This is a typical response that we have shown to be induced during tissue involution and/or decreased rate of cell proliferation (25 , 26) and is probably attributable to local cytotoxicity caused by growth of the tumor.
By means of the logistic regression analysis, we next sought to use the
changes in gene expression observed in the cancer tissues relative to
matched normal prostate to develop an alternative classification system
for prostate tumors. This was compiled using the data from the 18 CaPs
for which quantification of all of the transcripts had been carried out
(Table 2)
.
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the classification of patients was based only on the
expression of the markers of tissue proliferation and cell quiescence,
H3 and Gas1, respectively. Using this method, classification of 61.1%
of the patients coincided with the differentiation (Gleason) grade.
When the same patients were classified according to specific markers of
the S phase, H3 and ODC, this percentage increased to 66.7% (Table 2B)
, which is probably related to higher proliferation rate in higher
Gleason grade prostate cancers. Finally, when all of the genes studied
were used to produce the classification, the overall prediction in
72.2% of the patients coincided with the differentiation grade (Table 2C)
. When used to discriminate between organ confined or locally
invasive CaP, the levels of H3 and Gas1 gene
expression were able to predict tumor localization in 72.2% of the
patients (Table 3A)
, including all of the genes in the analysis brought the overall
prediction to 83.3% (organ confined, 75%; capsular penetration 100%;
Table 3B
). Thus, the molecular classification was generally in good
agreement with both the Gleason grade and local invasiveness.
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and
3B
)
were predicted as
belonging to the nearest group. Intriguingly, in two patients with
moderately differentiated CaPs, according to the Gleason grading, but
classified in the poorly differentiated group by the molecular
classification (using the complete gene set), the total PSA after
radical prostatectomy has now begun to rise, in a 1-year follow-up
period, to 2.0 and 0.5 ng/ml, respectively, suggesting the possibility
of tumor relapse. Conversely, in the two poorly differentiated tumors
that were ascribed by the molecular classification to the moderately
differentiated group, the total PSA after radical prostatectomy
remained constantly <0.1 ng/ml (Table 2C)
, indicative of successful
treatment. The molecular classification system correctly predicted all
of the tumors showing capsular penetration, when all of the genes were
included in the analysis (Table 3B)
. Three patients classified as
belonging to the organ-confined group were ascribed to the more
aggressive phenotype on the basis of gene expression. For two of them,
the probability of being included in the capsular penetration group was
56 and 51%, respectively. However for the third patient, whose
probability of being included in the capsular penetration group was
86%, the total PSA levels determined after surgery were constantly
increasing, and tumor relapse has now been demonstrated. These good correlations, even in a heterogeneous tumor like CaP, indicate that changes in expression of all of the genes studied in the CaP specimens are involved in tumor progression. Although neoplastic transformation is often the consequence of aberrant expression of oncogenes and tumor suppressor genes, it is also accompanied by disruption of the coordinate expression of set of genes controlling the levels of specific metabolites. In a tissue-specific manner, it is likely that more precise means for the classifications of tumor malignancy may result from the definition of expression profiles of these specific metabolically related sets of genes.
Longer patient follow-up should provide the information that will enable us to understand whether the particular features shown by this new taxonomic tool will be useful to provide new perspectives about CaP progression that cannot be obtained by the traditional systems and to augment the current available clinical tools.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was partially supported by:
"Associazione Angela Serra per la Ricerca sul Cancro," Modena,
Italy; Ministero dell’Università e della Ricerca Scientifica
(MURST) Rome, Italy–National Interest Research Programs. 
2 To whom requests for reprints should be
addressed, at Dipartimento di Scienze Biomediche, Università di
Modena e Reggio Emilia, Via G. Campi 287-41100 Modena, Italy. Fax:
39-059-428524; E-mail: corti.arnaldo{at}unimo.it
3 The abbreviations used are: SPD, spermidine;
SPM, spermine; ODC, ornithine decarboxylase; OAZ, ornithine
decarboxylase antizyme; SSAT, spermidine/spermine
N1-acetyltransferase; AdoMetDC,
adenosylmethionine decarboxylase; SGP-2, sulfated glycoprotein 2
(clusterin); Gas1, growth arrest-specific gene 1; GAPDH,
glyceraldehyde-3-phosphate dehydrogenase; PSA, prostate-specific
antigen; CaP, prostate cancer.
Received 8/ 2/99. Accepted 11/10/99.
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N. Xing, Y. Chen, S. H. Mitchell, and C. Y.F. Young Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells Carcinogenesis, March 1, 2001; 22(3): 409 - 414. [Abstract] [Full Text] [PDF]
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, normal; 
, cancerous.
The specific mRNA radioactive signals, obtained by Northern blot
analysis as in Fig. 1
, moderately differentiated
(Gleason grade 3; n = 7);