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Pathology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045 [T. Y., A. S. T., Y. N., R. H., K. M., C. M., S. H.], and Pathology Division, National Cancer Center Research Institute East, Kashiwa, Chiba 277-8577 [A. O.], Japan
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Mutational inactivation of APC results in the accumulation of cytoplasmic ß-catenin protein through the failure of proper degradation (4) . We reported previously the accumulation of ß-catenin in adenoma and adenocarcinoma tissues of FAP patients (5) . Mutations of ß-catenin itself in its glycogen synthase kinase 3ß phosphorylation sites render resistance to proteolytic degradation and are reported to occur in half of sporadic colorectal cancer cells with wild-type APC (6 , 7) . Thus, accumulation of ß-catenin is a common phenomenon in the majority of colorectal cancers.
Why the accumulation of ß-catenin initiates colorectal carcinogenesis
has still not been established. ß-catenin is a mediator of the
Wingless and Wnt signaling pathways (8)
. By forming a
complex with TCF/LEF DNA-binding proteins, ß-catenin acts as a
transcriptional coactivator (9)
. In fact, colorectal
cancer cell lines with mutated ß-catenin or APC show constitutively
active TCF/LEF transcription (10)
. Thus far, genes
including c-myc, cyclin-D1, matrilysin, TCF1, and peroxisome
proliferator-activated receptor 
have been reported to be the target
genes of the TCF/LEF and ß-catenin transcriptional complex
(11, 12, 13, 14)
. The whole picture of gene expression profiles
initiating early colorectal carcinogenesis is, however, still obscure.
TCF4 is a TCF/LEF family member expressed in intestinal epithelia (10) . TCF4 lacking an NH2-terminal ß-catenin binding site was reported to suppress specifically transactivation by the TCF4/ß-catenin complex in a dominant-negative manner (10) . In this study, a colorectal carcinoma cell line was engineered to induce the truncated dominant-negative TCF4 protein under the strict control of the tetracycline-regulatory system (15) . This cell line enabled us to pinpoint precisely the cellular and molecular changes after the inactivation of TCF4. We report here that the human MDR1 gene is transcriptionally regulated by the TCF4/ß-catenin complex and that aberrant expression of MDR1 occurs as an early event in colorectal carcinogenesis.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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N30, pEGFP-TCF4BN30, or pCR3.1-TCF4BN30,
respectively. The compositions of all of the constructs in this study
were confirmed by restriction endonuclease digestion and by sequencing.
Details of the procedures used for plasmid construction are available
on request.
A colon cancer cell line, DLD-1, was obtained from the Riken Cell Bank.
DLD-1 was double-transfected sequentially with regulatory pTet-ON
(Clontech) and responsive pTRE-TCF4BN30 plasmids using LipofectAMINE
PLUS (Life Technologies, Inc.). Three stable clones, DLD-1 Tet-ON
TCF4BN30–1, -5, and -7, all of which were capable of inducing
truncated TCF4BN30 in the presence of 2 µg/ml doxycyline (Sigma),
were isolated. The integration of empty pTRE plasmid DNA was confirmed
by PCR in four mock clones, DLD-1 Tet-ON control-A, -B, -C, and -D.
Two other colorectal cancer cell lines, SW48 and SW480, were purchased from the American Type Culture Collection. SW48 has a missense mutation at the glycogen synthase kinase 3ß phosphorylation site of ß-catenin, making the protein resistant to proteolysis (7) . SW480 has an APC gene truncated at codon 1338 and the loss of the other allele (7) .
Antibodies.
Anti-TCF4B rabbit polyclonal antibody was raised against a keyhole
limpet hemocyanin-conjugated synthetic peptide, CYKVKAAASAHPLQMEAY.
Monoclonal murine antibody against ß-catenin and an irrelevant
control monoclonal antibody of the same isotype (IgG1) were purchased
from Transduction Laboratories. Monoclonal antibodies against
P-glycoprotein, C494 and C219, were purchased from Dako Corporation.
C219 is known to react with both MDR1 and MDR3 gene products
(16)
.
Northern Blot and Western Blot Analyses.
Total RNA (15 µg/lane) was fractionated by electrophoresis and
transferred to Hybond N (Amersham). Hybridization was performed by
using 32P-radiolabeled cloned cDNA fragments of
MDR1 (nucleotides 382–912, accession number M14758) and TCF4B
(nucleotides 546-2015), as described previously (17)
. The
quality and quantity of electrophoresed RNA was determined by
hybridization with glyceraldehyde-3-phosphate dehydrogenase cDNA
(Clontech).
Western blot analyses were performed essentially as described
previously (17)
. The quality and quantity of
electrophoresed protein was determined by reblotting with
anti-Na+/K+-ATPase (
3
subunit) monoclonal antibody (Affinity Bioresearch; Ref.
5
).
cDNA Microarray Screening.
mRNA was prepared from DLD-1 Tet-ON TCF4BN30–7 cells treated with 2
µg/ml doxycycline for 48 h or from untreated cells. Two-color
fluorescence hybridization of cDNA microarray was performed by Genome
Systems, Inc. Two cDNA samples, labeled either with Cy3 or Cy5
fluorescent dyes, were applied competitively to a single UniGEM V
microarray, containing over 7000 human cDNA mapped in the UniGene
database.
Immunohistochemistry.
Ten FAP patients were selected from the surgical pathology panel of
National Cancer Center Central Hospital, 8 of whom have been described
previously (5)
. Formalin-fixed and paraffin-embedded
colorectal tissues containing adenoma (all 10 cases) and carcinoma (5
of 10 cases) were stained using the avidin-biotin complex method as
described previously (5
, 16)
.
Reporter Constructs and Luciferase Assay.
A fragment of the MDR1 gene promoter (-2028/+31; Ref.
18
) was fused upstream of the firefly luciferase gene in
pGL3-basic (Promega). The nested deletion mutants, listed in
Fig. 4D, were generated from this construct by digestion with
restriction endonucleases, blunting with T4 DNA polymerase and
recirculating with T4 DNA ligase.
Three copies of the 15-bp optimal TCF/LEF motif, CCCTTTGATCTTACC, or the mutant motif, CCCTTTgcCTTACC, (10) were subcloned into the MluI/BglII site of pGL3-promoter (Promega; pGL3-TOP and pGL3-FOP, respectively).
Cells were transiently transfected with reporters using LipofectAMINE PLUS in triplicate, and 48 h later luciferase activity was measured using a Luciferase assay system (Promega).
Gel Retardation Assay.
Nuclear extracts were prepared as described previously
(10)
. pCR3.1-TCF4BN30 or control pCR3.1 was transcribed
and translated in vitro using the TNT reticulocyte lysate
system (Promega). Double-stranded oligonucleotide probes were
32P-labeled using T4 polynucleotide kinase
(Takara Shuzo). The sequences of probes used for gel retardation assays
in this study are listed in Fig. 4A
. After incubating
radiolabeled probes with nuclear extracts or in vitro
translation products, in the presence or absence of excess cold
competitors, for 20 min under the conditions described previously
(10)
, the samples were incubated for an additional 20 min
with antibodies and then electrophoresed through nondenaturing 4%
polyacrylamide gel run in 0.25x TBE at room temperature.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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N30.
and four mock clones from DLD-1. In the presence of
doxycycline, DLD-1 Tet-ON TCF4BN30 clones induced truncated TCF4B
protein (Fig. 1B)
and mRNA (Fig. 2A)
in a time-dependent manner, but DLD-1 Tet-ON control cells
did not.
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revealed that DLD-1 Tet-ON TCF4BN30 clones maintained constitutive
TCF/LEF activity, as shown by the high luciferase activity driven by
the pGL3-TOP reporter carrying trimerized optimal sequences for TCF/LEF
and the low activity driven by the mutant reporter, pGL3-FOP
(uninduced, Fig. 1C
). In parallel with the induction of
dominant-negative TCF4B, the activity driven by pGL3-TOP was diminished
to the level of pGL3-FOP within 36 h (Fig. 1C)
. The
luciferase activity driven by pGL3-FOP was unaffected by the induction
of dominant-negative TCF4B. The same doxycycline treatment did not
affect the luciferase activity driven by pGL3-TOP and pGL3-FOP in mock
clones (data not shown).
Identification of MDR1 as a Target Gene of the
TCF4/ß-Catenin Complex.
We compared the gene expression profiles of DLD-1 Tet-ON TCF4BN30–7
cells treated with 2 µg/ml doxycycline for 48 h and those of
untreated cells using two-color fluorescence hybridization to cDNA
microarray. Among over 7000 genes examined, the expression of the
MDR1 gene was found to be significantly down-regulated upon
induction of the dominant-negative TCF4B.
Northern blot (Fig. 2A)
and Western blot (Fig. 2B)
analyses confirmed that the induction of
dominant-negative TCF4B suppressed the expression of the
MDR1 gene. The MDR1 cDNA probe used in this study was
selected from an unconserved region between MDR1 and MDR3 to avoid
cross-hybridization to MDR3 (19)
. DLD-1 transfectants did
not express the MDR3 gene at a level detectable by Northern
blot analysis (data not shown).
Aberrant Expression of MDR1 in Early Colorectal Carcinogenesis of
FAP Patients.
We examined colorectal tissues from 10 FAP patients
immunohistochemically. In all 10 cases, numerous adenomatous
polyps were observed throughout the resected colorectal specimens.
Invasive adenocarcinoma was observed in five cases. Serial sections
were stained with anti-ß-catenin and anti-P-glycoprotein (C494; Ref.
16
) monoclonal antibodies to explore their correlation.
ß-Catenin was stained intensely in differentiated epithelial cells
lining the luminal surface of nonneoplastic mucosa (Fig. 3C)
. Adenoma and adenocarcinoma cells showed intense
immunohistochemical reactivity with anti-ß-catenin antibody compared
with adjacent nonneoplastic epithelial cells (Fig. 3, A and C)
, as described previously (5)
. The cells that
stained intensely with anti-ß-catenin antibody also overexpressed the
MDR1 gene product in neighboring serial sections (Fig. 3, B and D)
. The glands that stained intensely with
the two antibodies were almost completely matched to each other. The
MDR1 gene product was localized along the entire cell
membrane in adenoma cells (Fig. 3E)
, but in adenocarcinoma
cells the expression of the MDR1 gene product tended to be
modest and limited to the inner surface of the glands (Fig. 3F)
. No immunoreactivity was observed with nonimmune mouse
IgG (data not shown).
|
. Double-stranded 15-bp oligomer probes containing these
core sequences (underlined) and their flanking sequences were examined
for binding to the TCF4/ß-catenin complex in gel retardation
assays. These canonical oligomers (Fig. 4
A, left) and
corresponding mutant oligomers (Fig. 4
A, right) were
designated 1–7 and 1mt–7mt, respectively. An optimal 15-bp
TCF/LEF-binding sequence (TOP) and its mutant (FOP), described by
Korinek et al. (10)
, were used as experimental
controls (data not shown) and cold competitors. The representative
autoradiograms are shown in Fig. 4, B and C
.
Using nuclear extracts from SW480 cells, we readily detected two
retarded bands in probes 1, 2, 3, and 5 (Fig. 4
B, Lane 1)
but not in 4, 6, and 7. The faster bands indicated the binding of
TCF/LEF protein to the radiolabeled probe, and the slower faint bands
indicated the binding of TCF/LEF and ß-catenin complex, as described
previously (7
, 10)
. The addition of excess TOP (Lane
3) or canonical (Lane 5) cold competitors abolished the
binding, but the addition of FOP (Lane 4) or mutant
(Lane 6) did not. The addition of anti-ß-catenin antibody
resulted in specific retardation of the latter band (arrowhead,
Lane 7) confirming the presence of ß-catenin in the complex.
Using products translated in vitro from the T7 promoter in
pCR3.1-TCF4BN30, we readily detected single retarded bands in the
canonical probes 1, 2, 3, and 5 (Fig. 4
C, Lane 1) but not in
4, 6, and 7. TCF4BN30 contains an intact high mobility group-box
DNA-binding domain (Fig. 1A)
. The addition of excess TOP
(Lane 5) or canonical (Lane 7) competitors
abolished the binding, but the addition of FOP (Lane 6) or
mutant (Lane 8) did not.
The MDR1 promoter luciferase construct containing -2028/+31 responded
to cotransfection with dominant-negative TCF4B (Fig. 4D)
.
The serial deletion of reporter constructs (Fig. 4
D, left)
reduced the responsiveness and the removal of -2028/-229 (which
excludes all possible TCF/LEF binding sites but still contains a basic
promoter) abolished the responsiveness (Fig. 4
D, right).
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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In this study, we established a colorectal carcinoma cell line capable of inducing the truncated dominant-negative TCF4 protein under the strict control of the tetracycline regulatory system. Through a large-scale comparison of >7000 genes by two-color fluorescence hybridization of cDNA microarray, MDR1 was found to be transcriptionally down-regulated after the inactivation of TCF4. Aberrant expression of MDR1, concomitant with the accumulation of ß-catenin, occurs even in small precancerous lesions of FAP patients. The promoter of the MDR1 gene contains multiple TCF4-binding sequences, concluding that MDR1 is a direct target gene of the TCF4/ß-catenin transcriptional complex.
Besides adenoma and carcinoma, ß-catenin accumulates in terminally
differentiated cells lining the luminal surface of nonneoplastic
intestinal mucosa (Fig. 3
C, left), implying a physiological
role of the TCF4/ß-catenin complex in intestinal cell
differentiation. Treatment with a differentiating agent, sodium
butyrate, up-regulates the TCF/LEF activity of colorectal cancer cell
lines (22)
, and consistently sodium butyrate has been
shown to enhance the expression of MDR1 (23)
. The
activation of the MDR1 promoter by sodium butyrate has been shown to be
mediated by the inhibition of histone deacetylases (24)
.
The p300/CBP acetyltransferases function as transcriptional
coactivators of ß-catenin (25)
.
Transactivation of MDR1 by the accumulated ß-catenin seems not to be limited to colorectal carcinogenesis. Mutational activation of ß-catenin is reported to be frequent in chemically induced adenomatous and carcinomatous liver nodules (26) . Increased expression of the mdr1 gene has been shown in similar experimental preneoplastic and neoplastic conditions (27) . Overexpression of P-glycoprotein has also been reported in adenomatous hyperplasia of human liver (28) .
The way in which overexpression of MDR1 is involved in colorectal carcinogenesis was not determined in the current study. The MDR1 gene product itself seems not to have transforming activity. Rapid turnover is a characteristic of intestinal epithelia. The intestinal stem cells continuously proliferate and give rise to a variety of committed cells. The integrity of the intestinal epithelium is maintained by proportional cell death of terminally differentiated cells. The failure of proper cell death disturbs the homeostatic turnover and may allow secondary genetic changes such as oncogenic activation of K-ras (3) . A colorectal cancer cell line HT29 has been shown to induce apoptosis by restoring wild-type APC (29) . MDR1, a downstream target of the APC pathway, may suppress cell death pathways programmed in intestinal cells by secreting endogenous or xenobiotic toxic substances into the intestinal lumen or by mediating a more generic antiapoptotic function (30) . The MDR1 gene product, P-glycoprotein, protects cells against a wide variety of caspase-dependent death stimuli, including FasL, tumor necrosis factor, and UV irradiation (30) .
Identification of MDR1 as a target of the TCF4/ß-catenin complex is of clinical importance, because several compounds that antagonize MDR1, such as verapamil and cyclosporin A, have been developed to treat MDR cancers (31) . The preventive efficacy of these compounds may be worth examining in multiple intestinal neoplasia (Min) mice (32) and subsequently in FAP patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This research was supported in part by a
Grant-in-Aid for the Second Term Comprehensive 10-Year Strategy for
Cancer Control from the Ministry of Health and Welfare, Japan.
A. S. T. and Y. N. are recipients of a Research Resident Fellowship
from the Foundation for Promotion of Cancer Research. 
2 To whom requests for reprints should be
addressed, at National Cancer Center Research Institute, Pathology
Division, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Phone:
81-3-3542-2511, extension 4101; Fax: 81-3-3248-2463; E-mail: shirohas{at}gan2.ncc.go.jp
3 The abbreviations used are: APC, adenomatous
polyposis coli; TCF, T-cell factor; LEF, lymphoid enhancer factor; MDR,
multidrug resistance; FAP, familial adenomatous polyposis.
Received 3/ 6/00. Accepted 7/19/00.
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is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell, 99: 335–345, 1999.
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)
or control pEGFP-C1 (
) into SW48 cells. Luciferase assays were
performed 48 h after transfection in triplicate.
Columns, mean luciferase activities;
bars, SD.
3 mm in size, with mild
to moderate atypia, in serial sections (x40).
Arrowheads, nonneoplastic glands. C and
D, adenoma with moderate atypia (right)
and adjacent nonneoplastic mucosa (left) of the colon in
serial sections (x200). E, a high-power view of adenoma
with moderate atypia (x400). F, invasive adenocarcinoma
(right) and adjacent nonneoplastic glands
(arrowheads, left) of the colon (x100).