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FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling.
[cholangiocarcinoma]
Interleukin
6
(
IL
-
6
)
-
mediated
signal
transducers
and
activators
of
transcription
3
(
STAT-
3
)
phosphorylation
(
activation
)
is
aberrantly
sustained
in
cholangiocarcinoma
cells
resulting
in
enhanced
myeloid
cell
leukemia
1
(
Mcl-
1
)
expression
and
resistance
to
apoptosis
.
FTY
720
,
a
new
immunosuppressant
,
derived
from
ISP-
1
,
has
been
studied
for
its
putative
anti-
cancer
properties
.
This
study
aimed
to
elucidate
the
mechanism
by
which
FTY
720
mediates
antitumor
effects
in
cholangiocarcinoma
(
CC
)
cells
.
Three
CC
cell
lines
were
examined
,
QBC
939
,
TFK-
1
,
and
HuCCT
1
.
The
therapeutic
effects
of
FTY
720
were
evaluated
in
vitro
and
in
vivo
.
Cell
proliferation
,
apoptosis
,
cell
cycle
,
invasive
potential
,
and
epithelial-
mesenchy-
mal
transition
(
EMT
)
were
examined
.
FTY
720
greatly
inhibited
CC
cells
proliferation
and
EMT
in
vitro
and
in
vivo
,
and
this
effect
was
associated
with
dephosphorylation
of
STAT
3
tyr
705
.
FTY
720
induced
apoptosis
and
G
1
phase
arrest
in
CC
cells
,
and
inhibited
invasion
of
CC
cells
.
Western
blot
analysis
showed
that
FTY
720
induced
cleavage
of
caspases
3
,
8
and
9
,
and
of
PARP
,
in
a
dose-dependent
manner
,
consistent
with
a
substantial
decrease
in
p
-
STAT
3
,
Bcl-x
L
,
Bcl-
2
,
survivin
,
cyclin
D
1
,
cyclin
E
,
N-
cadherin
,
vimentin
,
VEGF
and
TWIST
1
.
In
vivo
studies
showed
that
tumor
growth
and
metastasis
were
significantly
suppressed
after
FTY
720
treatment
.
These
results
suggest
that
FTY
720
induces
a
significant
decrease
in
p
-
STAT
3
,
which
inhibits
proliferation
and
EMT
of
CC
cells
,
and
then
induces
G
1
phase
arrest
and
apoptosis
.
We
have
characterized
a
novel
immunosuppressant
,
which
shows
potential
anti-
tumor
effects
on
CC
via
p
-
STAT
3
inhibition
.
FTY
720
merits
further
investigation
and
warrants
clinical
evaluation
.
Diseases
Validation
Diseases presenting
"tumor growth"
symptom
adrenal incidentaloma
carcinoma of the gallbladder
cholangiocarcinoma
cowden syndrome
cystinuria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
hodgkin lymphoma, classical
liposarcoma
lymphangioleiomyomatosis
primary effusion lymphoma
severe combined immunodeficiency
von hippel-lindau disease
waldenström macroglobulinemia
wiskott-aldrich syndrome
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