Resistance
to
platinum-based
chemotherapy
is
a
common
event
in
patients
with
cancer,
generally
associated
tumor
dissemination
and
metastasis.
Whether
platinum
treatment
per
se
activates
molecular
pathways
linked
spreading
not
known.
Here,
we
report
that
the
ubiquitin-specific
protease
1
(USP1)
mediates
ovarian
cancer
cell
resistance
platinum,
by
regulating
stability
of
Snail,
which,
turn,
promotes
dissemination.
At
level,
observed
upon
treatment,
USP1
phosphorylated
ATM
ATR
binds
Snail.
Then,
de-ubiquitinates
stabilizes
Snail
expression,
conferring
increased
stem
cell-like
features,
metastatic
ability.
Consistently,
knockout
or
pharmacological
inhibition
sensitivity
decreased
Snail-dependent
manner.
Our
findings
identify
as
target
open
way
novel
strategy
overcome
more
successfully
treat
cancer.
Journal of Hematology & Oncology,
Год журнала:
2022,
Номер
15(1)
Опубликована: Сен. 8, 2022
Abstract
Epithelial–mesenchymal
transition
(EMT)
is
an
essential
process
in
normal
embryonic
development
and
tissue
regeneration.
However,
aberrant
reactivation
of
EMT
associated
with
malignant
properties
tumor
cells
during
cancer
progression
metastasis,
including
promoted
migration
invasiveness,
increased
stemness,
enhanced
resistance
to
chemotherapy
immunotherapy.
tightly
regulated
by
a
complex
network
which
orchestrated
several
intrinsic
extrinsic
factors,
multiple
transcription
post-translational
control,
epigenetic
modifications,
noncoding
RNA-mediated
regulation.
In
this
review,
we
described
the
molecular
mechanisms,
signaling
pathways,
stages
tumorigenesis
involved
discussed
dynamic
non-binary
its
role
metastasis.
Finally,
summarized
challenges
immunotherapy
proposed
strategies
for
therapy
targeting
EMT.
Long
noncoding
RNAs
(lncRNAs)
have
emerged
as
critical
players
in
cancer
progression,
but
their
functions
colorectal
(CRC)
metastasis
not
been
systematically
clarified.lncRNA
expression
profiles
matched
normal
and
CRC
tissue
were
checked
using
microarray
analysis.
The
biological
roles
of
a
novel
lncRNA,
namely
RP11-138
J23.1
(RP11),
development
both
vitro
vivo.
Its
association
with
clinical
progression
was
further
analyzed.RP11
highly
expressed
tissues,
its
increased
stage
patients.
RP11
positively
regulated
the
migration,
invasion
epithelial
mesenchymal
transition
(EMT)
cells
enhanced
liver
Post-translational
upregulation
Zeb1,
an
EMT-related
transcription
factor,
essential
for
RP11-induced
cell
dissemination.
Mechanistically,
RP11/hnRNPA2B1/mRNA
complex
accelerated
mRNA
degradation
two
E3
ligases,
Siah1
Fbxo45,
subsequently
prevented
proteasomal
Zeb1.
m6A
methylation
involved
by
increasing
nuclear
accumulation.
Clinical
analysis
showed
that
can
regulate
RP11,
further,
Siah1-Fbxo45/Zeb1
CRC.m6A-induced
lncRNA
trigger
dissemination
via
post-translational
Considering
high
specific
levels
our
present
study
paves
way
investigations
predictive
biomarker
or
therapeutic
target
CRC.
The
Transforming
Growth
Factor-beta
(TGF-β)
family
plays
relevant
roles
in
the
regulation
of
different
cellular
processes
that
are
essential
for
tissue
and
organ
homeostasis.
In
case
liver,
TGF-β
signalling
participates
stages
disease
progression,
from
initial
liver
injury
towards
fibrosis,
cirrhosis
cancer.
When
a
chronic
takes
place,
mobilization
lymphocytes
other
inflammatory
cells
occur,
thus
setting
stage
persistence
an
response.
Macrophages
produce
profibrotic
mediators,
among
them,
TGF-β,
which
is
responsible
activation
-transdifferentiation-
quiescent
hepatic
stellate
(HSC)
to
myofibroblast
(MFB)
phenotype.
MFBs
principal
source
extracellular
matrix
protein
(ECM)
accumulation
prominent
mediators
fibrogenesis.
also
mediates
epithelial-mesenchymal
transition
(EMT)
process
hepatocytes
may
contribute,
directly
or
indirectly,
increase
MFB
population.
hepatocarcinogenesis,
dual
role,
behaving
as
suppressor
factor
at
early
stages,
but
contributing
later
tumour
once
escape
its
cytostatic
effects.
As
part
potential
pro-tumorigenic
actions,
induces
EMT
cells,
increases
pro-migratory
invasive
potential.
parallel,
changes
cell
plasticity,
conferring
properties
migratory
initiating
(TIC).
main
aim
this
review
shed
light
about
pleiotropic
actions
explain
effects
on
populations.
cross-talk
with
pathways
contribute
effects,
particular
Epidermal
Factor
Receptor
(EGFR),
will
be
presented.
Finally,
we
discuss
rationale
targeting
pathway
pathologies.
Signal Transduction and Targeted Therapy,
Год журнала:
2020,
Номер
5(1)
Опубликована: Окт. 7, 2020
Abstract
Resistance
to
cancer
therapy
is
a
major
barrier
management.
Conventional
views
have
proposed
that
acquisition
of
resistance
may
result
from
genetic
mutations.
However,
accumulating
evidence
implicates
key
role
non-mutational
mechanisms
underlying
drug
tolerance,
the
latter
which
focus
will
be
discussed
here.
Such
processes
are
largely
driven
by
tumor
cell
plasticity,
renders
cells
insusceptible
drug-targeted
pathway,
thereby
facilitating
survival
and
growth.
The
concept
plasticity
highlights
significance
re-activation
developmental
programs
closely
correlated
with
epithelial–mesenchymal
transition,
properties
stem
cells,
trans-differentiation
potential
during
exposure.
From
observations
in
various
cancers,
this
provides
an
opportunity
for
investigating
nature
anticancer
resistance.
Over
years,
our
understanding
emerging
phenotype
switching
modifying
therapeutic
response
has
considerably
increased.
This
expanded
knowledge
contributes
developing
novel
strategies
or
combination
regimens
using
available
drugs,
likely
improve
patient
outcomes
clinical
practice.
Organogenesis
is
crucial
for
proper
organ
formation
during
mammalian
embryonic
development.
However,
the
similarities
and
shared
features
between
different
organs
cellular
heterogeneity
this
process
at
single-cell
resolution
remain
elusive.
We
perform
RNA
sequencing
analysis
of
1916
individual
cells
from
eight
tissues
E9.5
to
E11.5
mouse
embryos,
namely,
forebrain,
hindbrain,
skin,
heart,
somite,
lung,
liver,
intestine.
Based
on
regulatory
activities
rather
than
expression
patterns,
all
analyzed
can
be
well
classified
into
four
major
groups
with
epithelial,
mesodermal,
hematopoietic,
neuronal
identities.
For
within
same
group,
differences
their
developmental
paths
are
revealed
reconstructed.
identify
mutual
interactions
epithelial
mesenchymal
detect
prevalent
organogenesis,
which
similar
intermediate
epithelial/mesenchymal
tumorigenesis.
The
comprehensive
transcriptome
profiled
in
our
study
paves
way
future
mechanistic
studies
gene-regulatory
networks
governing
organogenesis.
