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Areca nut components affect COX-2, cyclin B1/cdc25C and keratin expression, PGE2 production in keratinocyte is related to reactive oxygen species, CYP1A1, Src, EGFR and Ras signaling.
[oral submucous fibrosis]
Chewing
of
betel
quid
(
BQ
)
increases
the
risk
of
oral
cancer
and
oral
submucous
fibrosis
(
OSF
)
,
possibly
by
BQ-induced
toxicity
and
induction
of
inflammatory
response
in
oral
mucosa
.
P
rimary
gingival
keratinocytes
(
GK
cells
)
were
exposed
to
areca
nut
(
AN
)
components
with
/
without
inhibitors
.
Cytotoxicity
was
measured
by
3
-
(
4
,
5
-
dimethyl-
thiazol-
2
-
yl
)
-
2
,
5
-
diphenyl-tetrazolium
bromide
(
MTT
)
assay
.
mRNA
and
protein
expression
was
evaluated
by
reverse
transcriptase-polymerase
chain
reaction
(
RT-PCR
)
and
western
blotting
.
PGE
2
/
PGF
2
α
production
was
measured
by
enzyme-linked
immunosorbent
assays
.
Areca
nut
extract
(
ANE
)
stimulated
PGE
2
/
PGF
2
α
production
,
and
upregulated
the
expression
of
cyclooxygenase-
2
(
COX
-
2
)
,
cytochrome
P
450
1
A
1
(
CYP
1
A
1
)
and
hemeoxygenase-
1
(
HO
-
1
)
,
but
inhibited
expression
of
keratin
5
/
14
,
cyclinB
1
and
cdc
25
C
in
GK
cells
.
ANE
also
activated
epidermal
growth
factor
receptor
(
EGFR
)
,
Src
and
Ras
signaling
pathways
.
ANE-induced
COX
-
2
,
keratin
5
,
keratin
14
and
cdc
25
C
expression
as
well
as
PGE
2
production
were
differentially
regulated
by
α-naphthoflavone
(
a
CYP
1
A
1
/
1
A
2
inhibitor
)
,
PD
153035
(
EGFR
inhibitor
)
,
pp
2
(
Src
inhibitor
)
,
and
manumycin
A
(
a
Ras
inhibitor
)
.
ANE-induced
PGE
2
production
was
suppressed
by
piper
betle
leaf
(
PBL
)
extract
and
hydroxychavicol
(
two
major
BQ
components
)
,
dicoumarol
(
aQuinone
Oxidoreductase--
NQO
1
inhibitor
)
and
curcumin
.
ANE-induced
cytotoxicity
was
inhibited
by
catalase
and
enhanced
by
dicoumarol
,
suggesting
that
AN
components
may
contribute
to
the
pathogenesis
of
OSF
and
oral
cancer
via
induction
of
aberrant
differentiation
,
cytotoxicity
,
COX
-
2
expression
,
and
PGE
2
/
PGF
2
α
production
.
CYP
4501
A
1
,
reactive
oxygen
species
(
ROS
)
,
EGFR
,
Src
and
Ras
signaling
pathways
could
all
play
a
role
in
ANE-induced
pathogenesis
of
oral
cancer
.
Addition
of
PBL
into
BQ
and
curcumin
consumption
could
inhibit
the
ANE-induced
inflammatory
response
.
Diseases
Validation
Diseases presenting
"growth factor receptor"
symptom
achondroplasia
aromatase deficiency
cholangiocarcinoma
dedifferentiated liposarcoma
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
kallmann syndrome
lymphangioleiomyomatosis
oral submucous fibrosis
proteus syndrome
severe combined immunodeficiency
wiskott-aldrich syndrome
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