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Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma.
[dedifferentiated liposarcoma]
Fibroblast
growth
factor
(
FGF
)
receptor
(
FGFR
)
substrate
2
(
FRS
2
)
is
an
adaptor
protein
that
plays
a
critical
role
in
FGFR
signaling
.
FRS
2
is
located
on
chromosome
12
q
13
-
15
that
is
frequently
amplified
in
liposarcomas
.
The
significance
of
FRS
2
and
FGFR
signaling
in
high
-grade
liposarcomas
is
unknown
.
Herein
,
we
first
comparatively
examined
the
amplification
and
expression
of
FRS
2
with
CDK
4
and
MDM
2
in
dedifferentiated
liposarcoma
(
DDLS
)
and
undifferentiated
high
-grade
pleomorphic
sarcoma
(
UHGPS
)
.
Amplification
and
expression
of
the
three
genes
were
identified
in
90
%
to
100
%
(
9
-
11
of
11
)
of
DDLS
,
whereas
that
of
FRS
2
,
CDK
4
,
and
MDM
2
were
observed
in
55
%
(
41
of
75
)
,
48
%
(
36
of
75
)
,
and
44
%
(
33
/
75
)
of
clinically
diagnosed
UHGPS
,
suggesting
that
these
"
UHGPS
"
may
represent
DDLS
despite
lacking
histologic
evidence
of
lipoblasts
.
Immunohistochemical
analysis
of
phosphorylated
FRS
2
protein
indicated
that
the
FGFR
/
FRS
2
signaling
axis
was
generally
activated
in
about
75
%
of
FRS
2
-
positive
high
-grade
liposarcomas
.
Moreover
,
we
found
that
FRS
2
and
FGFRs
proteins
are
highly
expressed
and
functional
in
three
high
-grade
liposarcoma
cell
lines
:
FU-
DDLS
-
1
,
LiSa-
2
,
and
SW
872
.
Importantly
,
the
FGFR
selective
inhibitor
NVP-BGJ-
398
significantly
inhibited
the
growth
of
FU-
DDLS
-
1
and
LiSa-
2
cells
with
a
concomitant
suppression
of
FGFR
signal
transduction
.
Attenuation
of
FRS
2
protein
in
FU-
DDLS
-
1
and
LiSa-
2
cell
lines
decreased
the
phosphorylated
extracellular
signal-regulated
kinase
1
/
2
and
AKT
and
repressed
cell
proliferation
.
These
findings
indicate
that
analysis
of
FRS
2
in
combination
with
CDK
4
and
MDM
2
will
more
accurately
characterize
pathologic
features
of
high
-grade
liposarcomas
.
Activated
FGFR
/
FRS
2
signaling
may
play
a
functional
role
in
the
development
of
high
-grade
liposarcomas
,
therefore
,
serve
as
a
potential
therapeutic
target
.
Diseases
Validation
Diseases presenting
"potential therapeutic target"
symptom
alexander disease
canavan disease
dedifferentiated liposarcoma
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
familial mediterranean fever
heparin-induced thrombocytopenia
krabbe disease
liposarcoma
lymphangioleiomyomatosis
primary effusion lymphoma
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
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