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Short Communication |
From the Departments of Pathology,* InternalMedicine, and HumanGenetics, and The Comprehensive CancerCenter, The University of Michigan MedicalSchool, Ann Arbor, Michigan
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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, and
ITF2 genes in OEAs with deregulated ß-catenin. This
correlation was not observed for c-myc, another
putative ß-catenin/TCF-regulated gene. Immunohistochemical studies
confirmed that overexpression of cyclin D1 and MMP-7 was highly
associated with nuclear accumulation of ß-catenin and mutational
defects of the Wnt/ß-catenin/TCF-signaling pathway. Our findings
indicate cyclin D1, MMP-7, connexin 43,
PPAR-, and ITF-2, likely play important roles in the
pathogenesis of those OEAs that manifest defects in ß-catenin
regulation.
Defects in the Wnt signaling pathway seem to play a very significant
role in human cancer. Mutations in the CTNNB1 gene sequences
that encode the crucial GSK3ß phosphorylation sites in ß-catenin’s
N-terminal domain have been found in many different cancer
types.4-14
Inactivating mutations in the APC,
AXIN1, or AXIN2 tumor suppressor genes in
colorectal and selected other cancer types seem to inhibit
formation of the functional complex necessary for phosphorylation
of ß-catenin.4,15-18
In the case of APC, the
mutations may also interfere with the function of the APC protein in
exporting ß-catenin from the nucleus.19
A presumed
critical consequence of Wnt pathway mutations, whether in the
CTNNB1, APC, or AXIN genes, is
elevation of ß-catenin levels in the cytoplasm and nucleus.
Deregulation of ß-catenin leads to constitutive formation of
ß-catenin-TCF complexes and altered expression of TCF-regulated
target genes. The proteins encoded by these TCF-regulated genes
presumably play important roles in effecting neoplastic transformation.
Proposed ß-catenin/TCF target genes in cancer cells include
well-established oncogenes, such as c-myc and
CCND1 (Cyclin D1), as well as the
MMP-7 (matrix metalloproteinase
7/matrilysin), TCF7, LEF1,
PPAR- (peroxisome proliferator-activated
receptor delta), MDR1, WISP,
ID-2, CX43 (connexin 43), and
gastrin genes.20-32
Nearly all of these candidate ß-catenin/TCF-regulated genes have been
proposed based on data from in vitro or animal model
studies. Very few studies have evaluated expression of the presumptive
target genes in primary human tumors with documented mutational defects
in ß-catenin regulation. Of the published studies, nearly all have
focused on colorectal cancers. For instance, a strong correlation was
reported between ß-catenin deregulation and cyclin D1 and MMP-7
expression in primary colorectal tumors.33,34
Brabletz and
colleagues35
also found a tight correlation between
nuclear ß-catenin accumulation and c-myc expression in
colorectal adenomas, although neither feature correlated with grade of
dysplasia or proliferative activity. In hepatoblastomas, ß-catenin
mutations were strongly associated with cyclin D1, but not with
c-myc overexpression.36
The findings obtained
thus far suggest that only a subset of the proposed ß-catenin/TCF
target genes may play a key role in human cancer pathogenesis. An
alternative view is that at least some of the candidate ß-catenin/TCF
target genes have critical but not wide-ranging roles in cancer, with
certain candidate genes showing tissue-specific or context-specific
roles in cancers with ß-catenin deregulation. Therefore, given the
many uncertainties about the relationship between defective ß-catenin
regulation and specific gene expression changes in human cancer, we
sought to study expression of candidate ß-catenin/TCF target genes in
ovarian endometrioid adenocarcinoma (OEA), a tumor type known to have
mutations affecting ß-catenin regulation in upwards of half the
cases.37-40
Examining expression of candidate target
genes in OEAs with regulated versus deregulated
ß-catenin/TCF signaling should assist in identifying those target
genes of greatest relevance in the pathogenesis of OEAs and perhaps
other cancers. We report here on the analysis of 6 putative
ß-catenin/TCF target genes—namely, c-myc,
CCND1, PPAR-, ITF2 (immunoglobulin
transcription factor 2), CX43, and MMP-7–-in a
panel of 44 primary OEAs previously characterized for specific defects
in ß-catenin regulation.41
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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A total of 44 snap-frozen primary OEAs were analyzed. Five specimens were obtained from the Johns Hopkins Hospital; 2 from the University of Michigan Hospital; and 37 from the Cooperative Human Tissue Network/Gynecologic Oncology Group Tissue Bank. A small portion of formalin-fixed, paraffin-embedded tissue from each specimen was histologically verified as OEA by a gynecological pathologist (KRC), and classified as well differentiated, moderately differentiated, or poorly differentiated, based on the tumor’s histological features. Tumor stage (I to IV) was assigned according to the International Federation of Gynecology and Obstetrics system. Analysis of tissues from human subjects was approved by the University of Michigan’s Institutional Review Board (IRB-MED no. 2001-0568).
RNA and cDNA Preparation
Primary tumor tissues were manually microdissected before nucleic acid extraction to ensure each tumor sample contained at least 70% neoplastic cells. Hematoxylin- and eosin-stained sections of the frozen tumor tissues were used to guide dissection. Total RNA was extracted from pooled frozen tissue sections with Trizol (Life Technologies, Inc., Rockville, MD), according to the manufacturer’s protocol. First-strand cDNA was synthesized from DNase I-treated mRNA samples using random hexamer primers (Pharmacia Biotech, Piscataway, NJ) and Superscript II (Life Technologies, Inc.).
Ribonuclease (RNase) Protection Assay
Before RNase protection analysis, the integrity of primary
tumor RNA was monitored by electrophoresis on 1% agarose/MOPS gels.
Ethidium-bromide-stained gels were examined and only samples with
intact 28S and 18S ribosomal bands were studied further. cDNA fragments
used for generation of riboprobes were reverse transcriptase-polymerase
chain reaction products subcloned into pGEM-4Z (Promega, Madison, WI).
The length of the subcloned cDNA fragments were: L32 (76
bp), CX43 (180 bp), ITF2 (203 bp),
MMP-7 (226 bp), PPAR- (255 bp),
CCND1 (286 bp), and c-myc (320 bp). The different
probe lengths allowed their use in multiprobe reactions to conserve RNA
from primary tumor samples. The probe for the ribosomal L32
gene was generously provided by Dr. R. Rochford (University of Michigan
School of Public Health, Ann Arbor, MI).42
To synthesize
anti-sense probe sets, the pGEM-4Z subclones were linearized, and
32P-labeled riboprobes were synthesized using T7
RNA polymerase and the Riboprobe In Vitro Transcription
System (Promega). The final reaction contained 100 µCi of
[
-32P] UTP (3000 Ci/mmol; Amersham,
Arlington Heights, IL); 1 µl of ATP, CTP, GTP, and UTP mixture (2.5
mmol/L for ATP, CTP, and GTP; 10 µmol/L for UTP); 2 µl of
dithiothreitol (100 mmol); 1 µl of RNasin (40 U); 1 µl of T7
polymerase (10 U) and equal amounts of linearized probes (50 µg of
DNA for each probe). After 1 hour incubation at 37°C, reactions were
terminated by adding RQ1-DNase (2 U) for 30 minutes at 37°C. Labeled
probes were purified by phenol/chloroform extraction followed by
ethanol precipitation. The purified probe mix was then dissolved in 50
µl of hybridization buffer (80% formamide, 400 mmol/L NaCl, 1 mmol/L
ethylenediaminetetraacetic acid (EDTA), 40 mmol/L Pipes, pH 6.7) and
diluted to an activity of 5 x 105
cpm/2
µl. The probe set (2 µl) was added to tubes containing 5 µg of
total RNA in 8 µl of hybridization buffer, heated to 95°C for 2
minutes, then hybridized at 56°C overnight. Each sample was treated
with 25 ng of RNaseA (Boehringer Mannheim, Indianapolis, IN) and 75 U
of RNaseT1 (Promega) in 125 µl of digestion buffer (10 mmol/L Tris,
pH 7.5, 5 mmol/L EDTA, 30 mmol/L NaCl) for 45 minutes at 30°C. RNase
digestion was followed by addition of 1.5 µl of proteinase K (10
mg/ml) and 7 µl of 10% sodium dodecyl sulfate and incubation for 15
minutes at 37°C. The protected probes were extracted, precipitated,
and dissolved in loading buffer (80% formamide, 1 mmol/L EDTA, 50
mmol/L Tris-borate, pH 8.3), then separated by electrophoresis on 6%
denaturing polyacrylamide gels. Gels were analyzed by autoradiography
and the intensities of the specifically protected bands in gels were
quantitated by PhosphoImager Analysis (Molecular Dynamics, Wayzata,
MN). The expression level of each transcript species was determined
relative to the L32 transcript.
Immunohistochemical Analyses of Cyclin D1 and MMP-7 Expression
Five-µm sections of formalin-fixed, paraffin-embedded tissues were mounted on Probe-On slides (Fisher Scientific, Itasca, IL), deparaffinized in xylene, and then rehydrated into distilled H2O through graded alcohols. Antigen retrieval was enhanced by microwaving the slides for 15 minutes in citrate buffer (pH 6.0; Biogenex, San Ramon, CA) for the MMP-7 immunohistochemistry and in 1 mmol/L EDTA (pH 8.0; Fisher Scientific, Pittsburgh, PA) for the cyclin D1 immunohistochemistry. Endogenous peroxidase activity was quenched by incubation with 6% hydrogen peroxide in methanol, then the sections were washed and blocked with 1.5% normal horse serum for 1 hour. Sections were then incubated with a mouse monoclonal anti-MMP-7 antibody (MAB3315; Chemicon International, Inc. Temecula, CA) at a dilution of 1:500, or anti-cyclin D1 antibody (NCL-cyclinD1-GM; Novocastra Laboratories, Newcastle, UK) at a dilution of 1:50 overnight at 4°C. Slides were washed in phosphate-buffered saline, then incubated with a biotinylated horse anti-mouse secondary antibody for 30 minutes at room temperature. Antigen-antibody complexes were detected with the avidin-biotin peroxidase method using 3,3'-diaminobenzidine as a chromogenic substrate (Vectastain ABC kit; Vector Laboratories, Burlingame, CA). Immunostained sections were lightly counterstained with hematoxylin then examined by light microscopy. Immunoreactivity for cyclin D1 and MMP-7 was interpreted independently by two observers (YZ and RW). The results were scored semiquantitatively on the basis of cytoplasmic staining intensity for MMP-7 (-, no staining; ±, focally positive; +, weak; ++, moderate; +++, strong) and the percentage of positive nuclei for cyclin D1 (-, no positive cells; ±, <5%; +, 6 to 20%; ++, 21 to 50%; +++, >50%). For the rare cases with discordant scoring between the two observers, a final score was arrived at by consensus. Immunohistochemical analysis of ß-catenin expression in this particular set of tumors has been previously reported.41
Statistical Analysis
The Student’s t-test was used to determine the significance of differences in expression of candidate ß-catenin/Tcf target genes in OEAs with and without Wnt pathway defects. Tumors with documented CTNNB1 or APC mutations or unequivocally aberrant ß-catenin localization were categorized as tumors with pathway defects.41 After quantitation of the signals in the RNase protection experiments and normalization of the values to L32 expression, the mean expression and SD for each gene was assessed in the group of tumors with demonstrable defects in ß-catenin regulation. Similarly, the mean expression and SD for each gene was determined in the group of tumors with intact ß-catenin regulation. The difference in the expression of each candidate gene in the two groups of tumors was then assessed. Pearson correlation coefficients (r) were determined for comparisons between RNase protection and immunohistochemical expression data and between gene expression and ß-catenin mutational and regulation status. All statistical analyses were conducted using GraphPad Prism software (GraphPad Prism, Inc., San Diego, CA). A P value <0.05 was considered statistically significant for all analyses.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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As reviewed above, a number of candidate ß-catenin/Tcf target
genes have been suggested in the literature, including the
c-myc, CCND1, MMP-7,
PPAR-, and CX43
genes.20,21,23,26,27
Another gene, ITF2 (also
known as E2-2 or SEF2), which encodes a
helix-loop-helix transcription factor, has recently been implicated as
a potential ß-catenin/Tcf target gene (Kolligs and colleagues,
submitted). The expression of these six candidate
ß-catenin/Tcf target genes was evaluated using the ribonuclease
(RNase) protection assay, a sensitive and quantitative assay of gene
expression (Figure 1)
. Thirty-two of the
44 primary OEAs under study yielded RNA of suitable quality for the
RNase protection analysis (Table 1)
. The
32 tumors included 15 OEAs with definitively established or ostensible
Wnt/ß-catenin pathway defects [13 tumors with known
CTNNB1 mutations, and one tumor each with biallelic
inactivation of the APC gene (OE-32T), or diffuse strong
cytoplasmic ß-catenin immunoreactivity in the absence of membrane
staining (OE-15T)]. The remaining 17 tumors had wild-type
CTNNB1 alleles and membranous and/or weak cytoplasmic
ß-catenin immunoreactivity. The expression of each candidate
ß-catenin/Tcf target gene was determined by comparing the intensity
of the specific protected fragment in the RNase protection assay to the
intensity of the L32-specific fragment, using a
phosphoimager to measure signal intensities. The mean expression of
each candidate gene was then compared between the two groups of tumors
(ie, those tumors with defective ß-catenin regulation
versus those tumors with intact ß-catenin regulation).
OEAs with deregulated ß-catenin showed statistically significant
increases in expression of the MMP-7, CCND1,
CX43, PPAR-, and ITF2 genes
compared to tumors with intact ß-catenin regulation (Figure 2)
. In contrast, no difference in
c-myc expression was observed between the two tumor groups
(P = 0.64). The results of real-time
(quantitative) reverse transcriptase-polymerase chain reaction assays
for CCND1 and ITF2 showed excellent correlation
with the RNase protection results (data not shown).
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In an effort to determine whether the increased levels of
transcripts for candidate ß-catenin/TCF target genes was associated
with increased protein expression, we performed immunohistochemical
staining of the primary OEA tissues to evaluate expression of the two
genes with the highest transcript levels—MMP-7 and
CCND1. All 44 tumors proved suitable for the
immunohistochemical analysis. Based on our previous mutational and
immunohistochemical analyses of Wnt pathway defects in the OEA
specimens,41
16 of the 44 OEAs were found to have
persuasive evidence of defects in ß-catenin regulation. These 16
tumors included 14 tumors with CTNNB1 mutations,1 tumor with
biallelic inactivation of APC (OE-32T), and 1 tumor with
aberrant localization of ß-catenin protein by immunohistochemistry
(OE-15T). A tumor previously found to have a nonsense mutation in one
allele of AXIN1 (OE-29T) was grouped with the 28 tumors with
intact ß-catenin regulation, because neither biallelic inactivation
of AXIN1 nor aberrant localization of ß-catenin protein
could be demonstrated in the tumor. Cyclin D1 nuclear immunoreactivity
scores ranging from + to +++ (see Methods and Materials for scoring)
were observed in 11 of 16 (68.8%) tumors with deregulated ß-catenin
(Table 2
and Figure 3
; A to D), including 9 of the 14 tumors
with CTNNB1 mutations, OE-32T, and OE-15T. In contrast, only
2 of the 28 (7.1%) tumors with intact ß-catenin regulation showed
clearly positive reactivity for cyclin D1, with the remaining 26 tumors
showing negative or limited focal cyclin D1 staining (Table 2
and
Figure 3, E and F
).
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. However, tumors displayed very different
patterns depending on the status of ß-catenin. Strong (+++) or
moderate (++) staining for MMP-7 was seen in 9 of 14 tumors with
documented CTNNB1 mutations, as well as in OE-32T and OE-15T
(Table 2
and Figure 3, G and H
). Conversely, moderate MMP-7
immunoreactivity was observed in only 5 of the 28 (17.8%) tumors with
intact ß-catenin regulation, with the remainder showing only weak (+)
or negative MMP-7 expression (Table 2
and Figure 3, I and J
).
In our previous study, nuclear immunoreactivity for ß-catenin was
observed in 14 of the 44 OEAs.41
Notably, tumors with
nuclear accumulation of ß-catenin and/or CTNNB1 mutations
were always well or moderately differentiated. Nuclear ß-catenin
accumulation was significantly correlated with elevated MMP-7 and
cyclin D1 expression (r = 0.50,
P < 0.0006 and r = 0.77,
P < 0.0001, respectively). Elevated MMP-7 and cyclin
D1 expression were also tightly correlated with CTNNB1 gene
mutation (r = 0.52, P < 0.0004
and r = 0.61, P < 0.0001,
respectively) (Table 2)
. Moreover, the membrane-associated
ß-catenin-staining pattern, which we inferred here to reflect intact
ß-catenin regulation, did not correlate with MMP-7 overexpression
(r = -0.23) and showed a significant inverse
correlation with cyclin D1 overexpression (r =
-0.44, P < 0.003). Finally, we noted that, for both
MMP-7 and cyclin D1, elevated expression of RNA and protein were highly
concordant (r = 0.75, P <
0.0001 and r = 0.80, P < 0.0001,
respectively).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The gene encoding cyclin D1 (CCND1) has been identified as a key target gene regulated by the Wnt/ß-catenin pathway in colorectal cancer cells and possibly also in breast cancer.25,26,43 Our findings support the view that increased expression of cyclin D1 may also play a vital role in the pathogenesis of some OEAs. Interestingly, previous work demonstrated increased cyclin D1 expression in 5 to 32% of ovarian carcinomas, often in the absence of CCND1 amplification.44-47 Notably, in some of the studies, a predilection was observed for cyclin D1 overexpression in low-grade ovarian carcinomas and ovarian tumors of low malignant potential. The basis for this previous association may now be understood, at least in part, because OEAs with mutant ß-catenin are more frequently low grade, exhibit squamous differentiation, and are associated with a favorable prognosis.14,37,38
MMP-7 has been previously implicated as a ß-catenin/TCF-regulated target gene, in large part because of studies in murine and human intestinal tumors.27,33 A previous study has described increased expression of MMP-7 in ovarian carcinomas and tumors of low malignant potential, although no clear insights were offered into the basis for elevated MMP-7 in the tumors.48 In our analysis, primary OEAs with ß-catenin defects showed higher expression of MMP-7 mRNA and protein than did OEAs with intact ß-catenin regulation. However, a few (5 of 28) of the OEAs with intact ß-catenin regulation did show definite MMP-7 protein expression. This is not an entirely surprising result, as MMP-7 expression is likely to be regulated by multiple different signaling pathways. For instance, epidermal growth factor signaling seems to increase MMP-7 levels in human colon adenocarcinoma cells.49
Although the CX43 and PPAR- genes have been
identified as targets of the Wnt/ß-catenin signaling pathway in
certain cell types and contexts,20,23
neither gene has
been much studied in ovarian carcinomas. In fact, in one study,
connexin 43 was noted to be expressed at reduced levels in ovarian
carcinomas compared to normal ovarian surface epithelial
cells.50
Our data showing differences in the expression of
CX43 and PPAR- transcripts in OEAs with
ß-catenin defects versus OEAs with intact ß-catenin
regulation highlights the potential role of these two genes in ovarian
cancer development. Yet another potential ß-catenin/TCF target gene
in OEAs is the ITF2 gene (also known as E2-2 or
SEF2), which encodes a helix-loop-helix transcription factor
that may oligomerize with itself and potentially other helix-loop-helix
transcription factors, such as the E12 and E47 proteins and
MyoD.51-53
ITF2 has been implicated as a
potential ß-catenin/TCF target gene, primarily as the result of
studies in tissue culture model systems (Kolligs and colleagues,
submitted). The results of the studies presented here indicate
ITF2 deregulation may play a role in OEAs with defective
ß-catenin regulation and imply that further studies of the role of
ITF2 in other cancers with defects in ß-catenin regulation
may be of some interest.
c-myc was one of the first genes to be implicated as a ß-catenin/TCF-regulated target gene in cancer.21 However, previous studies of the relationship between ß-catenin deregulation in cancer and c-myc expression have yielded mixed results. For example, although a high degree of correlation between nuclear ß-catenin accumulation and overexpression of c-myc protein was seen in colon tumors,35 similar studies in hepatoblastoma and breast cancer found no such correlation.36,54 Studies in an in vitro model system in which mutant ß-catenin induces neoplastic transformation of rat epithelial cells also failed to implicate c-myc as a critical ß-catenin/TCF target gene.55 Our RNase protection assay revealed no correlation between the level of c-myc transcripts and the status of ß-catenin regulation in OEAs. In fact, on average, c-myc was expressed at modestly higher levels in the group of OEAs with intact regulation of ß-catenin than in the tumors with deregulated ß-catenin. Thus, despite the fact that elevated c-myc expression has been reported in upwards of 30% of ovarian cancers,56-58 it seems likely ß-catenin/TCF plays at best a minor role in altered c-myc expression in ovarian cancer, with gene amplification of c-myc likely playing a more prominent role, particularly in advanced stage serous carcinomas.
It should be noted that although the CCND1,
MMP-7, PPAR-, CX43, and
ITF2 genes were more highly expressed in the group of OEAs
with ß-catenin deregulation, the genes were not uniformly
up-regulated in all OEAs with defective ß-catenin regulation. Neither
were the genes uniformly expressed at low levels in all OEAs with
intact ß-catenin regulation. There are several possible explanations
for these results. It is possible that the status of ß-catenin
regulation was misclassified in some tumors. We think this explanation
is not a major factor in the cases under study, because we not only
characterized ß-catenin localization and levels by
immunohistochemistry in all 44 tumors, but we also carefully assessed
the mutational status of the Wnt/ß-catenin pathway genes known to be
mutated in cancers with observed deregulation of ß-catenin (ie, the
CTNNB1, APC, AXIN1, and
AXIN2 genes).41
Another possible explanation
for the absence of a strict correlation between ß-catenin defects and
gene expression is that variable expression of ß-catenin-binding
proteins, such as ICAT or Pin1,59,60
modulates ß-catenin
function and its ability to activate TCF-regulated target genes. Yet a
third possibility is that expression of one or more of the
ß-catenin/TCF target genes under study was substantially impacted by
alterations in other conserved signaling pathways and/or transcription
factor complexes. This explanation seems reasonable for at least some
of genes and tumors studied, as a number of candidate ß-catenin/TCF
target genes, including c-myc, CCND1, and
MMP-7, presumably lie downstream of diverse signaling
pathways and transcription factors. Further studies of gene expression
profiles in the panel of OEAs studied here should assist with
identification of novel downstream target genes in the Wnt/ß-catenin
pathway as well as efforts to define critical factors in ovarian cancer
pathogenesis.
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Footnotes |
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Supported by the National Institutes of Health grant CA 94172.
Y. Z. and R. W. contributed equally to this study.
Accepted for publication January 8, 2002.
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