miR-145 mediates TGF-β inhibition of CFTR synthesis and function in airway epithelia. Specific antagonists to miR-145 interrupt TGF-β signaling to restore F508del CFTR modulation. miR-145 antagonism may offer a novel therapeutic opportunity to enhance therapeutic benefit of F508del CFTR correction in CF epithelia.
Endoglin (
ENG
) regulates signaling by transforming growth factor‐
β
(
TGF
‐
β
), a genetic modifier of cystic fibrosis (
CF
) lung disease severity. We hypothesized that
ENG
mediates
TGF
‐
β
pathobiology in
CF
airway epithelia. Comparing
CF
and non‐
CF
human lungs, we measured
ENG
by
qPCR
, immunoblotting and
ELISA
. In human bronchial epithelial cell lines (16
HBE
), we used
CFTR
si
RNA
knockdown and functional inhibition (
CFTR
INH
‐172) to connect loss of
CFTR
to
ENG
synthesis. Plasmid overexpression of
ENG
assessed the direct effect of
ENG
on
TGF
‐
β
transcription and signal amplification in 16
HBE
cells. We found
ENG
protein to be increased more than fivefold both in human
CF
bronchoalveolar fluid (
BALF
) and human
CF
lung homogenates.
ENG
transcripts were increased threefold in
CF
, with a twofold increase in
TGF
‐
β
signaling.
CFTR
knockdown in 16
HBE
cells tripled
ENG
transcription and doubled protein levels with corresponding increases in
TGF
‐
β
signaling. Plasmid overexpression of
ENG
alone nearly doubled
TGF
‐
β
1
mRNA
and increased
TGF
‐
β
signaling in 16
HBE
cells. These experiments identify that loss of
CFTR
function increases
ENG
expression in
CF
epithelia and amplifies
TGF
‐
β
signaling. Targeting
ENG
may offer a novel therapeutic opportunity to address
TGF
‐
β
associated pathobiology in
CF
.
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