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Podocalyxin-like 1 promotes invadopodia formation and metastasis through activation of Rac1/Cdc42/cortactin signaling in breast cancer cells.
[wiskott-aldrich syndrome]
Metastatic
disease
is
the
leading
cause
of
cancer
mortality
.
Identifying
biomarkers
and
regulatory
mechanisms
is
important
toward
developing
diagnostic
and
therapeutic
tools
against
metastatic
cancer
.
In
this
study
,
we
demonstrated
that
podocalyxin-like
1
(
PODXL
)
is
overexpressed
in
breast
tumor
cells
and
increased
in
lymph
node
metastatic
cancer
.
Mechanistically
,
we
found
that
the
expression
of
PODXL
was
associated
with
cell
motility
and
invasiveness
.
Suppression
of
PODXL
in
MDA-
MB
-
231
cells
reduced
lamellipodia
formation
and
focal
adhesion
kinase
(
FAK
)
and
paxillin
phosphorylation
.
PODXL
knockdown
reduced
the
formation
of
invadopodia
,
such
as
inhibiting
the
colocalization
of
F-
actin
with
cortactin
and
suppressing
phosphorylation
of
cortactin
and
neural
Wiskott-
Aldrich
syndrome
protein
.
Conversely
,
overexpression
of
PODXL
in
MCF
7
cells
induced
F-
actin
/
cortactin
colocalization
and
enhanced
invadopodia
formation
and
activation
.
Invadopodia
activity
and
tumor
invasion
in
PODXL
-knockdown
cells
are
similar
to
that
in
cortactin
-knockdown
cells
.
We
further
found
that
the
DTHL
motif
in
PODXL
is
crucial
for
regulating
cortactin
phosphorylation
and
Rac
1
/
Cdc
42
activation
.
Inhibition
of
Rac
1
/
Cdc
42
impeded
PODXL
-mediated
cortactin
activation
and
FAK
and
paxillin
phosphorylation
.
Moreover
,
inhibition
of
PODXL
in
MDA-
MB
-
231
cells
significantly
suppressed
tumor
colonization
in
the
lungs
and
distant
metastases
,
similar
to
those
in
cortactin
-knockdown
cells
.
These
findings
show
that
overexpression
of
PODXL
enhanced
invadopodia
formation
and
tumor
metastasis
by
inducing
Rac
1
/
Cdc
42
/
cortactin
signaling
network
.
Diseases
Validation
Diseases presenting
"increased in lymph node metastatic cancer"
symptom
wiskott-aldrich syndrome
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