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Molecular Biology and Genetics |
B-dependent Expression of Metastasis Suppressor KAI1/CD82 Gene in Lung Cancer Cell Lines Expressing Mutant p531
Third Department of Internal Medicine, The University of Tokushima School of Medicine, Tokushima 770 [T. S., T. M., N. N., H. N., S. S.]; Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920 [N. M.]; and Department of Molecular Medicine, Sapporo Medical University, Sapporo 060 [H. H.], Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B, a key
molecule in TNF-mediated gene expression, is involved in the mechanism
of KAI1/CD82 induction. Our results demonstrated that
expression of KAI1/CD82 in PC-14 cells expressing mutant
p53 could be augmented by TNF-
, and that transfer of the gene for a
specific inhibitor of NF-B,
IBSR (mutant
IB; NF-B
super-repressor), into PC-14 cells could inhibit this
augmentation. The amount of NF-B in the nucleus of PC-14/IBSR
cells correlated well with KAI1/CD82 mRNA and protein expression. In
addition, IBSR gene
transfer inhibited the spontaneous expression of KAI1/CD82 protein in
KAI1/CD82-high-expressing RERF-LC-OK cells, which
contain a mutant-type p53. These observations indicate that NF-B
activation may play a role in the regulation of
KAI1/CD82 expression in lung cancer cells independently
of wild-type p53, and suggest that KAI1/CD82 expression
may be regulated by interaction with the host microenvironment. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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TNF, produced by various cell types including macrophages, endothelial cells, and cancer cells themselves during inflammatory reactions or tumor growth, is a central mediator of inflammation (7) . TNF has an ability to activate leukocytes, trigger local production of inflammatory cytokines, and enhance adherence of neutrophils, monocytes, and tumor cells to the intercellular matrix and endothelial cells; therefore, TNF mediates many of the cellular responses associated with the cytotoxicity of leukocytes and the invasion and metastasis of cancer cells (8) .
A pleiotropic transcription factor complex NF-B, which participates
in the regulation of genes coding for cytokines, cytokine receptors,
MHC antigens, adhesion molecules, and viruses including HIV-1,
plays a major role in the TNF-mediated activation of gene expression
(9)
. The active NF-B complex is composed of two
subunits designated p50 and p65 (10)
. In resting cells,
NF-B exists as an inactive form in the cytoplasm associated with the
inhibitory molecule IB (11)
. NF-B can be
activated by extracellular signals such as pro-inflammatory cytokines,
including TNF (12)
. When cells are stimulated by these
signals, IB is phosphorylated and then proteolytically degraded
and separates from NF-B. Then NF-B migrates into the nucleus,
where it activates target genes (13)
.
The present study was designed to determine whether TNF can affect
KAI1/CD82 expression in lung cancer cells and, if so,
whether NF-B is involved in the mechanism of regulation of
KAI1/CD82 gene expression. For this, we examined the
expression of KAI1/CD82 protein and mRNA in lung cancer cell lines with
or without TNF- treatment by FACS analysis and RT-PCR. We then
tested the effect of a specific inhibitor of NF-B,
IBSR (mutant
IB, NF-B super-repressor; Refs. 14
and 15
) gene transfer, on KAI1/CD82
expression.
Here, we present evidence to show the potential roles of NF-B
activation in KAI1/CD82 expression in lung cancer cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Reagents.
Production and characterization of murine mAb 53H5, which binds to
human CD82, were described previously (16)
. Anti-ICAM-1
antibody was purchased from Cosmo Bio Co. (Tokyo, Japan). Anti-MHC
class I and anti-CD9 antibody were from Immunotech (Marseille, France)
and anti-IB rabbit polyclonal antibody IB--(C-21) was from
Santa Cruz Biotechnology (California). TNF- (specific
activity, 3.25 x 105 Japanese reference
units/mg protein) was a gift from the Hayashibara Institute
(Okayama, Japan).
FACS Analysis of KAI1/CD82 Expression.
Cells (10, 6)
were resuspended in PBS
supplemented with 10% human pooled AB serum to prevent
nonspecific antibody binding. After incubation for 30 min at 4°C, the
cells were washed once and incubated for 30 min at 4°C in 2% FBS-PBS
containing 10 µg/ml each 53H5, anti-MHC class I, anti-ICAM-1,
anti-CD9 mAb, or mouse control serum (Tago, Inc., Burlingame,
CA). The cells were then washed with PBS, and fluorescein-conjugated
goat antimouse IgG (H+L; Immunotech, Marseille, France) was added as a
second antibody. After a 30-min incubation at 4°C, the cells were
washed again and the fluorescence intensity was measured with a FACScan
flowcytometer (Becton Dickinson, Mountain View, CA). Data files were
analyzed using CellQuest software (Becton Dickinson), and the channel
numbers were converged to linear values to compare the relative
intensities of logarithmically amplified signals. The relative
MFI of KAI1/CD82 was defined as the MFI of gated live cells
stained with 53H5/the MFI of cells stained with mouse control serum.
RT-PCR Analysis.
PC-14 variant cells incubated with 20 units/ml TNF- for the
indicated period and untreated RERF-LC-OK cells were lysed in ISOGEN
(Nippon Gene, Tokyo, Japan), a mixture of guanidinium isothiocyanate,
and phenol. Total cellular RNA was then extracted with chloroform and
precipitated with isopropanol. Continuous RT-PCR using avian
myeloblastosis virus reverse transcriptase and Taq DNA
polymerase was performed with 1 µg of total RNA using an
mRNA-selective PCR kit using the nucleotide analogue deoxynucleotide
triphosphate (TaKaRa, Tokyo, Japan). On the basis of the nucleotide
sequence of KAI1/CD82, 5'-ATGGGCTCAGCCTGTATCAA-3' was used
as the sense primer, and 5'-ATAGCAGCTGCCTCAGTACT-3' was used as the
antisense primer. This primer pair amplifies an 816-bp fragment
(nucleotides 166–981; Ref. 17
). In the case of
p53, 5'-CCTTCCCAGAAAACCTACCA-3' was used as the sense primer
and 5'-TCATAGGGCACCACCACACT-3' as the antisense primer; these
complementary sequences were located in exons 4 and 6, respectively,
and the amplification product was a 371-bp fragment (18)
.
ß-Actin DNA amplification was used as the internal PCR control; the
sense primer was 5'-AAGAGAGGCATCCTCACCCT-3' and the antisense primer
was 5'-TACATGGCTGGGGTGTTGAA-3' (19)
. The reaction mixture
(50 µl) was subjected to 30 PCR amplification cycles of 30 s at
85°C, 30 s at 40°C, and 90 s at 72°C. Five µl of the
amplified DNA samples were run on a 2% agarose gel, and bands were
visualized with ethidium bromide.
EMSA.
The oligomers used for the present study were the NF-B binding site
of the immunoglobulin light chain gene
(cagaGGGACTTTCCgaga; Ref. 20
) and the NF-B-like sequence of
the KAI1/CD82 gene (-371–362 bp, cagaGGGAGGgCCCgaga; Ref.
21
). Cancer cells were stimulated by the addition of 20
units/ml TNF-, or not stimulated, for 2 h. Nuclear proteins
were extracted according to the method described by Dignam et
al. (22)
. Nuclear proteins (8 µg) were
incubated with a 32P-labeled probe (2 x 104 cpm/reaction) and 0.5 mg/ml
poly(dI-dC) · Epoly(dI-dC) in 20 µl of binding buffer [20
mM HEPES (pH 7.9), 60 mM
KCl, 4 mM MgCl2, 0.2 mM
EDTA, 1 mM DTT, 10% (v/v) glycerol, and 2%
(v/v) polyvinyl alcohol] for 20 min at 25°C. In some experiments,
nuclear extracts were incubated with a 25- or 100-fold molar excess of
unlabeled oligomers for 10 min at 4°C before radiolabeled probe and
poly(dI-dC) · poly(dI-dC) were added. Samples were loaded onto 6%
polyacrylamide gels (acrylamide/N,N'-methylene bisacrylamide, 30:1) in
0.25x Tris borate buffer. After electrophoresis, gels were dried and
analyzed using an image analyzer (BAS 2000; Fuji Film Co., Tokyo,
Japan).
EMSA using a 32P-labeled oligomer identical to the p53 binding site of the KAI1/CD82 gene (-896 to -863 bp; Ref. 6 ) was also performed.
Generation of Retrovirus-producing Cells.
A deletion mutant of IB missing the
NH2-terminal 36 amino acids, including two
phosphorylation sites was used as IBSR (15)
and
cloned into pLXSN. The resulting plasmid was termed pLXSN/IBSR.
DNA transfection was carried out by the high-efficiency calcium
phosphate coprecipitation method. PA317 cells were transfected with
pLXSN/IBSR or pLXSN and then selected with 600 µg/ml of G418.
The resulting G418-resistant cells were pooled and used as
retrovirus-producing cells.
IBSR Gene Transduction.
PC-14 or RERF-LC-OK cells were plated at 5 x 104 cells/100-mm dish in medium containing 6 µg/ml of
polybrene (Aldrich, Milwaukee, WI), and transduced with LXSN/IBSR
or LXSN retrovirus-containing cell supernatant. The transduced cells
were then selected with 600 µg/ml of G418. The resulting
G418-resistant cells were pooled and used as transduced cells.
LXSN/IBSR-transduced cells and LXSN-transduced cells were termed
PC-14/IBSR or OK/IBSR and PC-14/LXSN or OK/LXSN,
respectively.
Western Blot Analysis of IBSR.
Cellular proteins were extracted according to the method described
previously (23)
. Samples of 60 µg of cellular lysates
were resolved by SDS-PAGE using a 10–20% gradient gel and transferred
to a nitrocellulose membrane. The membrane was blocked in PBS with
0.1% Tween 20 containing 5% nonfat milk for 6 h at 4°C. After
blocking, the membrane was incubated with a 1:1000 dilution of
IB--(C-21) for 1 h at room temperature. The immunoblots were
incubated for 45 min with a 1:1000 dilution of horseradish
peroxidase-linked sheep antirabbit IgG antibody (Amersham) and then
with an enhanced chemiluminescence reagent.
Statistical Analysis.
Differences in results obtained in cytofluorometry were evaluated by
Student’s two-tailed t test. In all determinations,
differences were considered significant at P < 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, human lung cancer cell lines constitutively expressed
KAI1/CD82 at a wide range of levels, and the expression in RERF-LC-OK
(OK) was highest among these cell lines.
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. on the expression of
KAI1/CD82 in the same human lung cancer cell lines by incubating
these cells in medium with 40 units/ml cytokine for 3 days
before FACS analysis and found that KAI1/CD82 in lung cancer cells
could be augmented by TNF-, and that PC-14 was most responsive to
TNF- treatment (Fig. 1B)
. Time-kinetic analysis showed
that KAI1/CD82 expression in PC-14 cells treated with TNF- reached a
maximal level by 24 h after stimulation, and that the induction by
TNF- was dose-dependent and reached a plateau at 20 units/ml (data
not shown).
We then examined the effects of TNF- on KAI1/CD82 mRNA
expression. As shown in Fig. 2A
, TNF-a could induce the expression of high level of
KAI1/CD82 mRNA in PC-14 cells. The induction reached a maximum
after 16 h of stimulation. Consistent with the low level of the
spontaneous expression of KAI1/CD82 protein in PC-14 cells,
KAI1/CD82 mRNA was detectable in unstimulated PC-14 cells when the
gel was loaded with a sufficient amount of PCR product or when the
numbers of PCR amplification cycles were increased (data not shown).
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, in
which an increased level of KAI1/CD82 mRNA was induced (Fig. 2B)
.
NF-B Activation in TNF--treated PC-14 Cells.
Nuclear extracts from unstimulated PC-14 cells or PC-14 cells
stimulated with TNF- were analyzed by a EMSA using
32P-labeled oligonucleotides containing the
immunoglobulin light-chain NF-B consensus sequence or the
NF-B-like sequence of the KAI1/CD82 gene. Increased
amounts of nuclear NF-B were clearly detectable in cells treated
with TNF- (Fig. 3
, Lanes 1 and 2). The specificity of the NF-B
mobility shift was confirmed by its prevention with the addition of an
excess of the unlabeled immunoglobulin light-chain NF-B
probe (Fig. 3
, Lanes 3 and 4). The same
mobility shift was unaffected by the addition of an excess of the
unlabeled oligonucleotides containing the NF-B-like sequence of the
KAI1/CD82 gene (Fig. 3
, Lanes 5 and
6). Moreover, a specific mobility-shifted band was not
detected when the 32P-labeled KAI1/CD82
NF-B-like probe was used (Fig. 3
, Lanes 7 and
8).
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light-chain NF-B probe, a small amount of mobility-shifted band was
detected (data not shown).
Inhibition of TNF--induced Up-Regulation of KAI1/CD82 on PC-14
Cells by PDTC.
We examined the effect of PDTC, which has the ability to block NF-B
activation independently of the inducing agent and cell line
(24)
, on the up-regulation of KAI1/CD82 expression induced
by TNF-. PC-14 cells were treated with 100 mM PDTC for
24 h, supplemented with TNF- (20 units/ml), and then cultured
for another 24 h. As shown in Table 1
, PDTC could block the augmentation of expression of not only MHC class
I molecules and ICAM-1, for which NF-B acts as a transcription
factor, but also the expression of KAI1/CD82 on PC-14 cells induced by
TNF-. On the other hand, the expression of CD9, another member of
the TM4SF, was slightly suppressed by TNF-, and PDTC did not affect
this suppression.
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B
(IBSR) Gene Transfer
for Inhibition of TNF--induced Up-Regulation of KAI1/CD82 on PC-14
Cells.B effect, but also metal-ion
chelating activities, we tested the effect of a specific inhibitor of
NF-B, IBSR, on the KAI1/CD82 expression in PC-14 cells using a
recombinant retroviral vector. After G418 selection, transduced cells
were cloned by limiting dilution, and their ability to express
IBSR was evaluated. Because IBSR is missing the
NH2-terminal 36 amino acids, the molecular weight
is smaller than that of endogenous IB. The transduced cells,
therefore, showed two bands in Western blot analysis using
anti-IB antibody IB--(C-21), which binds to the
COOH-terminal sequence. As shown in Fig. 4A
, we isolated two clones with the ability to express high
(clone 3) and intermediate (clone 10) levels of
IBSR, and then the mixed population, which expressed a low level
of IBSR, and two clones were further characterized. As shown in
Fig. 4B
, IkBSR gene transfer could
inhibit the activation of NF-B induced by TNF- in correlation
with the level of IBSR expression, and the amounts of NF-B in
the nucleus also correlated well with those of KAI1/CD82 mRNA (Fig. 4C)
and protein expression (Fig. 5
and Table 2
) in PC-14 cells. Unlike MHC class I molecules, ICAM-1 and KAI1/CD82,
CD9 expression was unaffected by
IBSR gene transfer (Table 2)
.
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BSR Gene Transfer
on KAI1/CD82-high-expressing RERF-LC-OK Cells.B activation was expected in this cell line. Therefore,
we also tested the effect of IBSR on the expression of these
proteins on RERF-LC-OK cells. Although the transduction efficiency was
very low, IBSR gene transfer
inhibited spontaneous expression of MHC class I molecules, ICAM-1 and
KAI1/CD82 on RERF-LC-OK cells, as expected (Table 3)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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augments the
KAI1/CD82 expression in lung cancer cell lines, and that
NF-B activation is involved in the mechanism of regulation of
KAI1/CD82 gene expression. Transfer of the gene for
IBSR, a specific inhibitor of NF-B, inhibited the activation
of NF-B induced by TNF-, and the amount of NF-B in the nucleus
correlated well with KAI1/CD82 gene and protein expression
in PC-14 cells (Fig. 4
, Table 2
). In addition, IBSR
gene transfer inhibited the spontaneous expression of this protein on
KAI1/CD82-high-expressing RERF-LC-OK cells (Table 3)
.
The NF-B activation in PC-14 cells induced by TNF- was not
completely blocked by IBSR gene
transfer, and weak KAI1/CD82 mRNA and protein induction were still
observed (Fig. 4, B and C)
, perhaps because
endogenous wild-type IB in the mutant-transfected cell lines
(Fig. 4A)
was degraded following TNF- treatment, leading
to NF-B activation despite the expression of the mutant IB.
A previous study by Mashimo et al. (6)
using
human prostatic cancer cell lines identified the p53-responsive element
in the 5' upstream region of the KAI1 gene (-892 to -868)
and revealed that wild-type p53, for which NF-B seems to be a
transcription factor (25)
, can directly activate
KAI1/CD82 gene expression by interacting with this site.
However, the p53 of PC-14 is a so-called contact mutant with a mutation
of the Arg248 residue, which is directly involved in DNA-binding
(26
, 27)
, and increased amounts of p53 mRNA were not
detectable in TNF--treated PC-14 cells, which showed increased
KAI1/CD82 mRNA expression (Fig. 2B)
. In addition, EMSA using
a p53-related oligomer did not show p53 protein accumulation in
TNF--treated PC-14 cells (data not shown). Moreover, the
p53 of RERF-LC-OK has been reported to be a functionally
mutant type as shown by functional analysis of separated alleles in
yeast (28)
. These data indicate that p53 does
not play a major role in KAI1/CD82 promoter activation in these lung
cancer cell lines.
The promoter region of the KAI1/CD82 gene has no TATA or
CCAAT box and, like other genes with TATA-less promoters, has many
putative binding motifs for various transcription factors, including
nine Sp1 sites and five AP2 sites (21)
. However, the
KAI1/CD82 promoter sequence does not include a putative NF-B binding
site, and EMSA indicated that NF-B cannot bind the NF-B-like
sequence of the promoter region of the KAI1/CD82 gene (-371
to -362; Ref. 21
; Fig. 3
). A possible explanation is that
NF-B acts as a transcription regulatory factor for another protein
that directly activates KAI1/CD82 gene expression or
increases the mRNA stability, or that some yet-undetected physical
interaction between NF-B and some other transcription factor(s), a
phenomenon termed cross-coupling (29
, 30)
, is required for
their cooperative activation of KAI1/CD82 gene.
One characteristic common to target genes of NF-B is their rapid
induction. Precursors of the activating complex are present in the
cytoplasm, and simple dissociation from the inactive complex does not
require new protein synthesis (31)
. However, the effect of
TNF- on KAI1/CD82 mRNA induction in PC-14 cells was not rapid (Fig. 2A)
. These results suggest the possibility that some
unidentified factor mediates the relationship between the
NF-B-stimulation and KAI1/CD82 mRNA induction.
NF-B is a transcription factor that has been shown to be associated
with increased cell survival in many tumor cells. Numerous studies have
revealed that the mechanisms in tumor cells that inhibit the apoptotic
response induced by chemotherapy (32, 33, 34)
, radiation
(35
, 36)
, or TNF (37
, 38)
involve NF-B
activation. These data suggest that the NF-B
family could be considered to be proto-oncogenes. On the other hand,
IB is a possible tumor suppressor, and antisense IB
treatment results in oncogenic transformation (39)
. In the
case of IBSR gene-transduced
RERF-LC-OK cells, after G418 selection for 2 weeks, several
G418-resistant colonies that showed decreased KAI1/CD82
expression were obtained (Table 3)
; however, stable transfectants could
not be obtained by additional culturing, suggesting that the inhibition
of NF-B is toxic for cells in which NF-B is constitutively
activated.
MRP-1, which is identical to CD9, also belongs to the TM4SF and
suppresses cell motility and metastasis (40)
.
Although its precise biological functions remain unknown, several
reports have shown that MRP-1/CD9 and KAI1/CD82 seem to act by similar
mechanisms (41, 42, 43, 44)
. In the present study, however,
TNF- slightly suppressed MRP-1/CD9 expression, in
contrast to the KAI1/CD82 induction, and an NF-B
inhibitor did not affect the TNF--inducible suppression or
spontaneous expression of MRP-1/CD9 (Tables 1
and 2)
. These
observations indicate that MRP-1/CD9 and
KAI1/CD82 gene expression are regulated differently and
independently of each other.
It is not evident as yet whether in vivo NF-B status of
NSCLC affects KAI1/CD82 expression and prognosis. At
present, mechanisms by which KAI1/CD82 may act as a
metastasis suppressor for NSCLC remains unclear. Recently, there is
accumulating evidence that anti-inflammatory cytokines, such as IL-4
and IL-10, negatively control NF-B activation and inhibit
inflammatory cytokine production (45
, 46)
, and that these
cytokines are detectable at NSCLC lesions in significant
concentration (47)
. In view of these results and the data
presented here on the NF-B dependent pathway for
KAI1/CD82 expression, one possible explanation for reduced
expression of KAI1/CD82 in human NSCLC, which is associated
with a poor prognosis (5)
, may be that anti-inflammatory
cytokines in the tumor microenvironment reduce KAI1/CD82
expression through NF-B inhibition.
In summary, our results revealed potential roles of NF-B activation
in KAI1/CD82 expression in lung cancer cells. These findings
suggest that the level of in vivo KAI1/CD82
expression may change during inflammatory reactions or tumor
progression. Because NF-B can up-regulate other factors that
contribute to the malignant phenotype, this transcription factor may
have dual roles in human lung cancer metastasis. Because several
clinical reports have indicated that KAI1/CD82 expression
cannot necessarily prevent metastasis (48)
, additional
studies concerning the relationship between the p53 status
and NF-B activation may be necessary as part of the evaluation of
the clinical effects of KAI1/CD82.
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FOOTNOTES |
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1 The present study was supported by a
Grant-in-Aid for Cancer Research from the Ministry of Education,
Science and Culture of Japan. 
2 To whom requests for reprints should be
addressed, at Third Department of Internal Medicine, The University of
Tokushima School of Medicine, 3-18-15 Kuramoto-cho, Tokushima 770,
Japan.
3 Abbreviations: TM4SF, transmembrane 4
superfamily; KAI, kang ai (Chinese for anticancer); NSCLC, non-small
cell lung cancer; TNF, tumor necrosis factor; NF, nuclear factor; FACS,
fluorescence-activated cell sorting; RT-PCR, reverse
transcription-PCR; FBS, fetal bovine serum; mAb, monoclonal antibody;
MFI, mean fluorescence intensity; PDTC, pyrrolidine dithiocarbamate;
EMSA, electrophoretic mobility shift assay; MRP-1, motility-related
protein-1.
Received 5/ 9/00. Accepted 11/14/00.
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