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Arecoline-induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated by ZEB1.
[oral submucous fibrosis]
Oral
submucous
fibrosis
(
OSF
)
is
considered
as
a
pre-cancerous
condition
of
the
oral
mucosa
and
is
highly
associated
with
habitual
areca
quid
chewing
.
Arecoline
is
the
major
alkaloid
in
areca
quid
and
is
thought
to
be
involved
in
the
pathogenesis
of
OSF
.
Our
previous
studies
have
demonstrated
that
arecoline
could
induce
epithelial-mesenchymal
transition
(
EMT
)
-
related
factors
in
primary
human
buccal
mucosal
fibroblasts
(
BMFs
)
.
Therefore
,
we
investigated
the
expression
of
zinc
finger
E
-
box
binding
homeobox
1
(
ZEB
1
)
,
which
is
a
well-known
transcriptional
factor
in
EMT
,
in
OSF
tissues
and
its
role
in
arecoline-induced
myofibroblast
transdifferentiation
from
BMFs
.
The
expression
of
ZEB
1
,
as
well
as
the
myofibroblast
marker
α-smooth
muscle
actin
(
α-
SMA
)
,
was
significantly
increased
in
OSF
tissues
,
respectively
.
With
immunofluorescence
analysis
,
arecoline
induced
the
formation
of
α-
SMA
-
positive
stress
fibres
in
BMFs
expressing
nuclear
ZEB
1
.
Arecoline
also
induced
collagen
contraction
of
BMFs
in
vitro
.
By
chromatin
immunoprecipitation
,
the
binding
of
ZEB
1
to
the
α-
SMA
promoter
in
BMFs
was
increased
by
arecoline
.
The
promoter
activity
of
α-
SMA
in
BMFs
was
also
induced
by
arecoline
,
while
knockdown
of
ZEB
1
abolished
arecoline-induced
α-
SMA
promoter
activity
and
collagen
contraction
of
BMFs
.
Long
-term
exposure
of
BMFs
to
arecoline
induced
the
expression
of
fibrogenic
genes
and
ZEB
1
.
Silencing
of
ZEB
1
in
fibrotic
BMFs
from
an
OSF
patient
also
suppressed
the
expression
of
α-
SMA
and
myofibroblast
activity
.
Inhibition
of
insulin
-like
growth
factor
receptor-
1
could
suppress
arecoline-induced
ZEB
1
activation
in
BMFs
.
Our
data
suggest
that
ZEB
1
may
participate
in
the
pathogenesis
of
areca
quid-associated
OSF
by
activating
the
α-
SMA
promoter
and
inducing
myofibroblast
transdifferentiation
from
BMFs
.
Diseases
Validation
Diseases presenting
"long-term exposure"
symptom
oral submucous fibrosis
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