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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
"short disease-specific survival"
symptom
esophageal squamous cell carcinoma
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