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MicroRNA-21 is induced by rapamycin in a model of tuberous sclerosis (TSC) and lymphangioleiomyomatosis (LAM).
[lymphangioleiomyomatosis]
Lymphangioleiomyomatosis
(
LAM
)
,
a
multisystem
disease
of
women
,
is
manifest
by
the
proliferation
of
smooth
muscle
-like
cells
in
the
lung
resulting
in
cystic
lung
destruction
.
Women
with
LAM
can
also
develop
renal
angiomyolipomas
.
LAM
is
caused
by
mutations
in
the
tuberous
sclerosis
complex
genes
(
TSC
1
or
TSC
2
)
,
resulting
in
hyperactive
mammalian
Target
of
Rapamycin
(
mTOR
)
signaling
.
The
mTOR
inhibitor
,
Rapamycin
,
stabilizes
lung
function
in
LAM
and
decreases
the
volume
of
renal
angiomyolipomas
,
but
lung
function
declines
and
angiomyolipomas
regrow
when
treatment
is
discontinued
,
suggesting
that
factors
induced
by
mTORC
1
inhibition
may
promote
the
survival
of
TSC
2
-
deficient
cells
.
Whether
microRNA
(
miRNA
,
miR
)
signaling
is
involved
in
the
response
of
LAM
to
mTORC
1
inhibition
is
unknown
.
We
identified
Rapamycin-dependent
miRNA
in
LAM
patient
angiomyolipoma
-derived
cells
using
two
separate
screens
.
First
,
we
assayed
132
miRNA
of
known
significance
to
tumor
biology
.
Using
a
cut-off
of
>
1
.
5
-
fold
change
,
48
microRNA
were
Rapamycin-induced
,
while
4
miRs
were
downregulated
.
In
a
second
screen
encompassing
946
miRNA
,
18
miRs
were
upregulated
by
Rapamycin
,
while
eight
were
downregulated
.
Dysregulation
of
miRs
29
b
,
21
,
24
,
221
,
106
a
and
199
a
were
common
to
both
platforms
and
were
classified
as
candidate
"
RapamiRs
.
"
Validation
by
qRT-PCR
confirmed
that
these
microRNA
were
increased
.
miR-
21
,
a
pro-survival
miR
,
was
the
most
significantly
increased
by
mTOR-inhibition
(
p
<
0
.
01
)
.
The
regulation
of
miR-
21
by
Rapamycin
is
cell
type
independent
.
mTOR
inhibition
promotes
the
processing
of
the
miR-
21
transcript
(
pri-mi
R-
21
)
to
a
premature
form
(
pre-mi
R-
21
)
.
In
conclusion
,
our
findings
demonstrate
that
Rapamycin
upregulates
multiple
miRs
,
including
pro-survival
miRs
,
in
TSC
2
-
deficient
patient-derived
cells
.
The
induction
of
miRs
may
contribute
to
the
response
of
LAM
and
TSC
patients
to
Rapamycin
therapy
.
Diseases
Validation
Diseases presenting
"deficient cells"
symptom
child syndrome
esophageal adenocarcinoma
gm1 gangliosidosis
junctional epidermolysis bullosa
kindler syndrome
lymphangioleiomyomatosis
neonatal adrenoleukodystrophy
werner syndrome
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