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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
"cancer"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
alpha-thalassemia
benign recurrent intrahepatic cholestasis
cadasil
canavan disease
carcinoma of the gallbladder
cholangiocarcinoma
coats disease
congenital adrenal hyperplasia
congenital diaphragmatic hernia
cowden syndrome
cushing syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erdheim-chester disease
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
familial hypocalciuric hypercalcemia
familial mediterranean fever
gm1 gangliosidosis
heparin-induced thrombocytopenia
hereditary cerebral hemorrhage with amyloidosis
hirschsprung disease
hodgkin lymphoma, classical
inclusion body myositis
junctional epidermolysis bullosa
kabuki syndrome
kallmann syndrome
kindler syndrome
lamellar ichthyosis
liposarcoma
locked-in syndrome
lymphangioleiomyomatosis
monosomy 21
neuralgic amyotrophy
oculocutaneous albinism
oligodontia
oral submucous fibrosis
papillon-lefèvre syndrome
pendred syndrome
pleomorphic liposarcoma
primary effusion lymphoma
proteus syndrome
pyomyositis
pyruvate dehydrogenase deficiency
severe combined immunodeficiency
sneddon syndrome
systemic capillary leak syndrome
triple a syndrome
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated