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Departments of Pathology [B-J. P., J-H. P., S-G. Chi.] and Urology [Se-J. L., J. I. K., Su-J. L., C-H. L., S-G. Cha.], School of Medicine, Kyung Hee University, Seoul 130-701, Korea
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Np63, in 63
bladder specimens. In 12 normal tissues, TAp63 was
expressed at an easily detectable level whereas
Np63 was absent or extremely low.
While none of 47 carcinomas showed allelic deletion of the gene, marked
reduction of TAp63 and abnormal overexpression of
Np63 were found in 25 (53.2%) and 30
(63.8%) carcinomas, respectively. Tumor-specific alteration of
TAp63 and Np63
expression was identified in two and three of six matched sets,
respectively. In addition, reduced expression of TAp63
showed a correlation with tumor stage and grade. Abnormal expression of
TAp63 or Np63 isoform
was also observed in three of four cell lines, and treatment with
5-Aza-2'-deoxycytidine led to up- or down-regulation of
TAp63 and/or Np63
expression, suggesting that the promoters of both isoforms might be
affected by DNA methylation, but not in a reciprocal fashion. No
sequence alteration of p63 was identified in 47
carcinomas whereas 17 (34.8%) of these showed p53
mutations, and no association between p63 expression and
the mutational status of p53 or expression of
p21Waf1, MDM2, and
14–3-3
was recognized. Our data suggest that altered
expression of p63 is a frequent event in bladder
carcinogenesis and might contribute to the progression of bladder
tumors, possibly via the mechanism(s) distinct from the p53 pathway. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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However, there are currently no genetic evidences that inactivation of p73 is required for transformation or malignant progression of human tumors, except recent reports of epigenetic silencing of p73 by aberrant 5'CpG island methylation in specific types of hematological malignancies such as acute lymphoblastic leukemia, lymphoblastic lymphomas, and Burkitt’s lymphoma (10 , 11) . Several studies also showed more intense and/or biallelic expression of wild-type p73 in various types of tumors than in normal tissues, which suggested that overexpression of p73 rather than as tumor suppressor may contribute to the tumorigenesis (12 , 13) . Recently, we also reported an elevated and biallelic expression of p73 in bladder carcinomas, which argues that p73 does not play a role as a tumor suppressor in bladder carcinogenesis (14) .
p63 encodes multiple products with transactivating,
death-inducing, and dominant-negative activities, which are derived
from a single gene with two promoters (TAp63 and
Np63) and at least three alternative splicing
of the transcripts (
, ß, and 
; Refs. 4, 5, 6, 7
). TAp63
isotypes with the acidic NH2-terminal
transactivating domain can activate transcription of p53 target genes
such as p21Waf1, whereas Np63
isoforms without the transactivating domain can act as
dominant-negative factors toward transactivation by p53 and p63
(4
, 6)
. p63 is highly expressed in proliferating basal
cells of epithelial layers, including epidermis, cervix, urothelium,
and prostate, and the major p63 isoforms in these basal cells lack the
transactivating domain (4
, 6)
. Recent studies revealed
that mutational alteration of p63 is uncommon in human
cancer cell lines and tumors (15
, 16)
. However, it was
demonstrated that expression of p63 is low or absent in a
subset of lung cancer and Np63 transcript is
dominantly expressed in cell lines with high levels of p63
expression (17)
. Expression of TAp63 was
also found to associate with tumor growth in cervical carcinogenesis,
and numbers of the cells expressing Np63 and
their distribution showed a correlation with anaplasia in squamous cell
carcinoma (18
, 19)
.
Although the genomic imbalance at 3q27–29 has not been directly implicated in human cancers, several genetic studies using microsatellites and comparative genomic hybridization demonstrated frequent loss of heterozygosity (3) or amplifications at several regions of chromosome 3 in bladder tumors (20 , 21) . In the present study, we performed expression and mutation analyses of p63 in 63 bladder specimens, including 47 primary carcinomas and four cell lines, to investigate the potential involvement of p63 alteration in the pathogenesis of bladder cancer. Here, we show that genomic deletion or mutations of p63 is uncommon in primary bladder carcinoma, but its altered expression might contribute to the progression of bladder tumors.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Quantitative PCR Analysis.
For quantitative evaluation by PCR, we initially performed the PCR
reaction over a range of cycles (24, 27, 30, 33, 36, 39, and 42
cycles). Diluted cDNA (1:4; 12.5 ng/50 µli
PCR reaction) undergoing 27–36 cycles was observed to be within the
logarithmic phase of amplification and yielded reproducible results
with the primers used for p63, p40–1 (sense,
5'-CCTGGACGTATTCCACTGAACT-3') and p40–2 (antisense,
5'-CGCTTCGTACCATCACCGTTCT-3'), and an endogenous expression standard
gene, GAPDH (14)
. For isoform-specific
quantitation of TAp63 and Np63,
primers TAp63–2 (sense, 5'-GACCTGAGTGACCCCATGTG-3') and p63–2
(antisense, 5'-TCTGGATGGGGCATGTCTTTGC-3') and primers
Np63–1 (sense, 5'-TGCCCAGACTCAATTTAGTGAG-3') and p63–2
(see above) were used, respectively. PCR was performed for 36 cycles at
95°C (1 min), 60–63°C (0.5 min), and 72°C (1 min) in 1.5
mM MgCl2-containing reaction buffer (PCR buffer
II; Perkin-Elmer Corp.). Ten microliters of
RT-PCR3
products were resolved on 2% agarose gels. Quantitation of expression
levels was achieved by densitometric scanning of the ethidium
bromide-stained gels. Absolute area integrations of the curves
representing each specimen were then compared after adjustment for
GAPDH expression. For quantitative DNA/PCR analysis of the
p63 gene, 200 ng of genomic DNA were used for amplification
of exon 5 of the gene with an intron-specific primers p63-E5S (sense,
5'-TCTCCTTCCTTTCTCCACTGGC-3') and p63-E5AS (antisense,
5'-TGCCCACAGAATCTTGACCTTC-3'). The GAPDH gene was used for
an endogenous control for quantitative DNA/PCR. Integration and
analysis were performed using Molecular Analyst software program
(Bio-Rad, Hercules, CA).
Nonisotopic RT-PCR-SSCP Analysis.
Nonisotopic RT-PCR-SSCP analysis was performed as described previously
(23)
. The p63 transcript was amplified with six
sets of primers that were designed to cover the entire coding region of
the gene. Sequences of the primers used for our PCR-SSCP analysis will
be obtained on request. The PCR products of over 300 bp in length were
digested with endonuclease(s) to increase the sensitivity of SSCP
analysis. Twenty microliters of PCR products were mixed with 5 µl of
0.5 N NaOH, 10 mM EDTA, 10 µl of denaturing
loading buffer (95% formamide, 20 mM EDTA,
0.05% bromphenol blue, and 0.05% xylene cyanol), and 15 µl of
ddH2O. After heating at 95°C for 5 min, samples
were loaded in wells precooled to 4°C. SSCP was performed using 8%
nondenaturating acrylamide gels containing 10% glycerol at 4–8°C or
18–22°C.
5-Aza-2'-Deoxycytidine Treatment.
To assess activation of p63 expression, four bladder
carcinoma cell lines were plated in 6-well tissue plates 24 h
before treatment. 5-Aza-2'-deoxycytidine (Sigma Chemical Co., St.
Louis, MO) was added to the fresh medium at concentrations of 1.0 and
2.0 µM in duplicate, and cells were harvested
after 3 and 5 days.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Np63 in 12 noncancerous bladder tissues by
quantitative RT-PCR using isoform-specific primers. As shown in Fig. 1
, expression of TAp63 mRNA was easily detectable in all
noncancerous tissues we examined, whereas expression of
Np63 was extremely low or not detected. No
significant variation in expression levels of p63
transcripts was recognized among the specimens (TAp63/GAPDH,
0.83–1.14; Np63/GAPDH, 0.00–0.28). On the
basis of this observation, we arbitrarily classified expression levels
less than a half (<0.49; levels 0–2 for TAp63) and more
than 2-fold (>0.38; levels 3–5 for Np63) of
noncancerous means as abnormal expression. Of four bladder
carcinoma cell lines examined, three (J82, T24, and HT1197) and
two (HT1197 and HT1376) were identified to express abnormally low
TAp63 and high Np63 mRNA,
respectively (Table 1)
.
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and Table 1
). In addition, tumor-specific reduction of
TAp63 was found in two of six matched sets (Fig. 2B)
. Interestingly, abnormally low expression (levels 0–2)
of TAp63 showed a correlation with tumor stage and grade
(Table 1)
. Whereas abnormal reduction of TAp63 was observed
in 28.0% (7 of 25) of superficial tumors (Ta-T1), 81.8% (18 of 22) of
invasive tumors (T2-T4) were identified as low or no TAp63
expressors. Low expression of TAp63 was also found in 38.9%
(7 of 18) of grade I, 43.8% (7 of 16) of grade II, and 84.6% (11 of
13) of grade III tumors. Thus, these observations demonstrate that
altered expression of TAp63 mRNA is a frequent event in
bladder carcinogenesis and suggest that inactivation of TAp63 might
contribute to the malignant progression of primary bladder tumors.
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Np63 in
Carcinomas.Np63
could act as a dominant-negative factor toward the
G1 cell cycle arrest and apoptosis induction by
TAp63 or p53 (4
, 6)
. In this context, we investigated the
possible involvement of abnormal Np63
elevation in bladder tumorigenesis. As shown in Fig. 2
, abnormally high
expression (levels 3–5) of Np63 was detected
in 63.8% (30 of 47) of carcinomas and tumor-specific increase of
Np63 was observed in three of six matched
sets. However, unlike TAp63, abnormal overexpression of
Np63 was not associated with tumor stage and
grade (Table 1)
.
Relationship between TAp63 and
Np63 Expression.
If Np63 acts as a dominant-negative factor toward
the growth inhibition or apoptosis by TAp63, alteration of
TAp63 and Np63 would be expected to
be mutually exclusive in cancer cells. Whereas 19 (86.4%) of 22 normal
expressors of TAp63 showed abnormally high
Np63, 11 (44.0%) of 25 tumors with low
TAp63 expression were identified as high
Np63 expressors (Table 2)
. Likewise, although 14 (82.4%) of 17 normal expressors of
Np63 showed abnormally low TAp63,
only 11 (36.7%) of 30 tumors with high Np63
expression were identified as low TAp63 expressors.
Similarly, two (J82 and T24) of the three cell lines with low
TAp63 expressed normal levels of
Np63, whereas the HT1376 cell line with a
normal level of TAp63 expressed abnormally high
Np63 (Fig. 1)
. However, simultaneous
alteration of TAp63 and Np63 was
also found in 11 (23.4%) of the 47 carcinomas and in one (25.0%) of
the four cell lines. Thus, a mutually exclusive expression pattern of
TAp63 and Np63 was recognized in
general, whereas a subset of tumors showed altered expression of both
isoforms.
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and p63 in
Bladder Tissues., p63ß, and p63, we
performed PCR amplification of the COOH-terminal portion of
p63 transcripts using variant-specific primer sets.
p63 and p63 transcripts were easily
detectable in all p63-positive tissues, and no significant
difference in expression levels of these two variants was recognized.
In contrast, expression of p63ß transcripts was not
detected under our experiment conditions (data not shown).
Absence of p63 Mutation and No Correlation with
p53 Status.
To investigate the allelic deletion or mutational alteration of the
p63 gene, we performed quantitative DNA/PCR and RT-PCR-SSCP
analyses of p63 for 47 primary carcinomas, four cell lines,
and 10 noncancerous tissues. Compared with normal tissues, no
significant difference was detected in p63 gene levels in
tumors, indicating that abnormal expression of p63 mRNA is
not associated with allelic alteration of the gene (Figs. 1
and 2)
. For
SSCP analysis, the entire coding region of the transcripts was
amplified using six different sets of primers, digested with several
different restriction endonucleases, and subjected to electrophoresis
under two different running conditions. However, we failed to detect
any types of mutation leading to amino acid substitutions or
frameshifts, whereas 36.2% (17 of 47) of the same set of primary
carcinomas was identified to carry p53 mutations. Thus, this
result indicates that, unlike p53, mutational alteration of
p63 is not a main genetic event in the bladder
carcinogenesis. In addition, no correlation was identified between
altered expression of p63 isoforms and p53 status
in tumors we analyzed (Table 2)
. To further define the possible
association of p63 with the p53 pathway, we
examined expression of p53 target genes such as
p21Waf1, MDM2, and
14–3-3. Whereas low expression of
p21Waf1 mRNA was more frequently observed
in tumors with p53 mutation (11 of 17, 64.7%) than tumors
with wild-type p53 (4 of 30, 13.3%), alteration of
TAp63 or Np63 showed no association
with mRNA expression of p53 target genes (Table 2)
. Taken
together, these data demonstrate that alteration of p63
expression does not correlate with the mutational status of
p53 and its target gene expression in bladder carcinomas.
Biphasic Effect of 5-Aza-2'-Deoxycytidine on p63
Expression.
To explore whether abnormal methylation is associated with the altered
expression of p63, we treated the four cell lines with a
demethylating agent, 5-Aza-2'-deoxycytidine, and analyzed expression
levels of TAp63 and Np63. Whereas
expression of TAp63 mRNA was induced in T24 by
5-Aza-2'-deoxycytidine treatment, up- and down-regulation of both
TAp63 and Np63 transcriptions were
observed in HT1376 and HT1197, respectively, and no change in
p63 levels was detected in J82 (Fig. 3)
. These results suggest that abnormal hypermethylation would be one of
the causes for the altered expression of p63, but other
factors might be implicated in the reciprocal regulation of
TAp63 and Np63 in bladder
carcinoma.
|
, expression of TAp63 (P = 0.06)
but not Np63 (P = 0.88) was recognized to correlate with cumulative survival of the
patients after operation.
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Np63 is a frequent event and might
contribute to the progression of bladder tumors. Our study also
suggests that alteration of p63 expression might be caused
by more complicated mechanisms, including epigenetic factors rather
than allelic or mutational alteration of the gene. It has been
previously reported that expression of p63, predominantly
Np63, is highly expressed in basal cells with
high proliferative potential and is absent from the cells that are
undergoing terminal differentiation (4
, 6)
. A recent study
also showed that p63 expression is absent or low in a
considerable proportion of lung cancers and
Np63 transcript is dominantly expressed in
cell lines with high levels of p63 expression, whereas only
1 of 44 cell lines but none of 45 primary tumors has p63
mutation (15)
. In squamous cell carcinoma of the skin, the
number and distribution of cells expressing
Np63 was found to correlate with anaplasia
(19)
. In this context, it is noteworthy that a mutually
exclusive alteration of TAp63 and
Np63 was recognized in a substantial fraction
of bladder tumors we analyzed, and low TAp63 rather than
high Np63 expression showed a correlation with
tumor stage and grade. However, our finding of simultaneous alteration
of TAp63 and Np63 expression in a
subset of tumors also raises the possibility that two isoforms of
p63 might carry their specific roles in bladder
carcinogenesis. This hypothesis is partly supported by our observation
that altered expression of TAp63 is correlated with tumor
progression and patient survival but no further increase of
Np63 alteration is observed in advanced
tumors, suggesting its possible contribution to an initial step of
bladder tumorigenesis. Further study will be required to gain
understanding for the biological significance of isoform-specific roles
of p63 in human tumorigenesis.
It has been hypothesized that disruption of normal p53 function results
in compensatory or deleterious up-regulation of other members of the
p53 gene family or that overexpressed Np63 may bind p53
DNA target sites in a competitive manner or mimic mutant p53, thus act
as a dominant-negative factor in wild-type p53-carrying
tumor cells (3, 4, 5, 6)
. However, recent studies demonstrated
that p63 transactivates the p53 target genes but the degree of the
transactivation by p63 differed from that by p53, and the tumor-derived
p63 missense mutations were found to retain their ability to
transactivate the MDM2 and/or the Bax promoter
but not the p21Waf1 promoter, indicating
that the cellular signal on p63 cross-talks partially, but not
completely, with that of the p53 pathway (24
, 25)
. It has
been also observed that p53 in cancer cells was not able to interact
with endogenous or exogenous p63 or p73 via their respective
oligomerization domains while the multiple isoforms of p63, as well as
those of p73, are capable of interacting via their common
oligomerization domain (26)
. Moreover, recent studies
showed that p53-inactivating viral oncoproteins such as SV40 T antigen,
human papilloma virus E6, and adenovirus E1B do not directly interact
with p63 and do not inhibit p63-mediated transcription, suggesting that
unlike p53, p63 does not seem to be a necessary target in virus-induced
cell transformation (27
, 28)
. Consistent with these
observations, we identified no association of TAp63 or
Np63 expression with the mutational status of
p53 and the expressions of p53 target genes such as
p21Waf1, MDM2, and
14–3-3 in primary bladder tumors and cell lines. Our
preliminary work also showed that transient overexpression of wild-type
p53 or p73, treatment with a DNA-damaging agent
(etoposide), or cell growth under growth factor-deprived culture
condition did not significantly affect the expression levels of both
TAp63 and Np63 mRNA in bladder
carcinoma cell lines (data not shown). Taken together, these results
suggest that p63 may not exert a role comparable with p53
and be involved in an unknown tumor suppressor pathway distinct from
that of p53.
Recent studies demonstrated that mutations in the p63 gene are rare in human cell lines and tumors. Hagiwara et al. (15) reported that only 2 of 54 human cell lines have either heterozygous mutations or polymorphisms in the putative DNA binding domain of p63. Other investigators identified only four distinct missense mutations of p63 after screening >200 tumors and cell lines (5 , 16) . In the present study, we also failed to detect allelic deletion or any types of mutation leading to amino acid change of p63 in bladder cancers whereas 36.2% of the same tumors were identified to carry p53 mutations. This result indicates that mutational alteration of p63 may be not a main genetic event in the bladder carcinogenesis and suggests that p63 is unlikely to be a tumor suppressor gene that conforms to a two-hit model of tumorigenesis.
In conclusion, the evidences we obtained here clearly demonstrate that
p63 is not a target of sequence alterations in bladder
carcinogenesis, but abnormal reduction of TAp63 and/or
overexpression of Np63 are frequent and might
contribute to the progression of bladder cancer, although the
functional significance of p63 alteration was not defined in
the present work. Additional studies will be required to elucidate the
roles of altered p63 expression in growth and apoptosis of
bladder epithelial cells.
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FOOTNOTES |
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1 These authors contributed equally to this
work. 
2 To whom requests for reprints should be
addressed at, Department of Pathology, College of Medicine, Kyung Hee
University, 130-701 Seoul, Republic of Korea. Phone: 02-961-0920; Fax:
02-960-2871; E-mail: sgchi{at}nms.kyunghee.ac.Kr
3 The abbreviations used are: RT-PCR, reverse
transcription-PCR; SSCP, single-strand conformation polymorphism;
GAPDH, glyceraldehydes-3-phosphate dehydrogenase.
Received 1/ 7/00. Accepted 5/17/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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, a p53 homolog, in non-small cell lung cancer and breast cancer. Oncogene, 18: 3761-3765, 1999.[Medline]
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K. Hibi, S.-i. Fujitake, T. Takase, Y. Kodera, K. Ito, S. Akiyama, M. Shirane, and A. Nakao Identification of S100A2 as a Target of the {Delta}Np63 Oncogenic Pathway Clin. Cancer Res., September 15, 2003; 9(11): 4282 - 4285. [Abstract] [Full Text] [PDF]
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 C. Langner, M. Ratschek, O. Tsybrovskyy, L. Schips, and R. Zigeuner P63 Immunoreactivity Distinguishes Upper Urinary Tract Transitional-cell Carcinoma and Renal-cell Carcinoma Even in Poorly Differentiated Tumors J. Histochem. Cytochem., August 1, 2003; 51(8): 1097 - 1099. [Abstract] [Full Text] [PDF]
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G. Wu, S. Nomoto, M. O. Hoque, T. Dracheva, M. Osada, C.-C. R. Lee, S. M. Dong, Z. Guo, N. Benoit, Y. Cohen, et al. {Delta}Np63{alpha} and TAp63{alpha} Regulate Transcription of Genes with Distinct Biological Functions in Cancer and Development Cancer Res., May 15, 2003; 63(10): 2351 - 2357. [Abstract] [Full Text] [PDF]
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 M. J. Urist, C. J. Di Como, M.-L. Lu, E. Charytonowicz, D. Verbel, C. P. Crum, T. A. Ince, F. D. McKeon, and C. Cordon-Cardo Loss of p63 Expression Is Associated with Tumor Progression in Bladder Cancer Am. J. Pathol., October 1, 2002; 161(4): 1199 - 1206. [Abstract] [Full Text] [PDF]
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 A. I. Zaika, N. Slade, S. H. Erster, C. Sansome, T. W. Joseph, M. Pearl, E. Chalas, and U. M. Moll {Delta}Np73, A Dominant-Negative Inhibitor of Wild-type p53 and TAp73, Is Up-regulated in Human Tumors J. Exp. Med., September 16, 2002; 196(6): 765 - 780. [Abstract] [Full Text] [PDF]
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S. Strano, G. Fontemaggi, A. Costanzo, M. G. Rizzo, O. Monti, A. Baccarini, G. Del Sal, M. Levrero, A. Sacchi, M. Oren, et al. Physical Interaction with Human Tumor-derived p53 Mutants Inhibits p63 Activities J. Biol. Chem., May 17, 2002; 277(21): 18817 - 18826. [Abstract] [Full Text] [PDF]
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H. Nishi, M. Senoo, K. H. Nishi, B. Murphy, T. Rikiyama, Y. Matsumura, S. Habu, and A. C. Johnson p53 Homologue p63 Represses Epidermal Growth Factor Receptor Expression J. Biol. Chem., November 2, 2001; 276(45): 41717 - 41724. [Abstract] [Full Text] [PDF]
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C. Gaiddon, M. Lokshin, J. Ahn, T. Zhang, and C. Prives A Subset of Tumor-Derived Mutant Forms of p53 Down-Regulate p63 and p73 through a Direct Interaction with the p53 Core Domain Mol. Cell. Biol., March 1, 2001; 21(5): 1874 - 1887. [Abstract] [Full Text]
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 E. A. Ratovitski, M. Patturajan, K. Hibi, B. Trink, K. Yamaguchi, and D. Sidransky p53 associates with and targets Delta Np63 into a protein degradation pathway PNAS, February 13, 2001; 98(4): 1817 - 1822. [Abstract] [Full Text] [PDF]
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