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Inhibition of human positive cofactor 4 radiosensitizes human esophageal squmaous cell carcinoma cells by suppressing XLF-mediated nonhomologous end joining.
[esophageal squamous cell carcinoma]
Radiotherapy
has
the
widest
application
to
esophageal
squamous
cell
carcinoma
(
ESCC
)
patients
.
Factors
associated
with
DNA
damage
repair
have
been
shown
to
function
in
cell
radiosensitivity
.
Human
positive
cofactor
4
(
PC
4
)
has
a
role
in
nonhomologous
end
joining
(
NHEJ
)
and
is
involved
in
DNA
damage
repair
.
However
,
the
clinical
significance
and
biological
role
of
PC
4
in
cancer
progression
and
cancer
cellular
responses
to
chemoradiotherapy
(
CRT
)
remain
largely
unknown
.
The
aim
of
the
present
study
was
to
investigate
the
potential
roles
of
PC
4
in
the
radiosensitivity
of
ESCC
.
In
this
study
,
we
showed
that
knockdown
of
PC
4
substantially
increased
ESCC
cell
sensitivity
to
ionizing
radiation
(
IR
)
both
in
vitro
and
in
vivo
and
enhanced
radiation-induced
apoptosis
and
mitotic
catastrophe
(
MC
)
.
Importantly
,
we
demonstrated
that
silencing
of
PC
4
suppressed
NHEJ
by
downregulating
the
expression
of
XLF
in
ESCC
cells
,
whereas
reconstituting
the
expression
of
XLF
protein
in
the
PC
4
-
knockdown
ESCC
cells
restored
NHEJ
activity
and
radioresistance
.
Moreover
,
high
expression
of
PC
4
positively
correlated
with
ESCC
resistance
to
CRT
and
was
an
independent
predictor
for
short
disease-
specific
survival
of
ESCC
patients
in
both
of
our
cohorts
.
These
findings
suggest
that
PC
4
protects
ESCC
cells
from
IR-induced
death
by
enhancing
the
NHEJ-promoting
activity
of
XLF
and
could
be
used
as
a
novel
radiosensitivity
predictor
and
a
promising
therapeutic
target
for
ESCCs
.
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