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Zhang Z
; Qu J
; Zheng C
; Zhang P
; Zhou W
; Cui W
; Mo X
; Li L
; Xu L
; Gao J
Cell Death Dis
2018[Jan]; 9
(2
): 83
PMID29362432
show ga
Epithelial mesenchymal transition (EMT) is a key progression that promotes
pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is
implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its
downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1
(NQO1) constitute an important pathway of antioxidant defense signal for
protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and
Numb have a potential relationship in EMT-mediated PF. Here, we observed the
effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout
(Nrf2(-/-)) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial
cells line (RLE-6TN) and human epithelial cells line (A549) were both treated
with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb
to unravel roles of Nrf2 pathway, Numb and the link between them on transforming
growth factor ?1 (TGF-?1)-induced EMT. We found BLM-induced lung fibrosis were
more severe in Nrf2(-/-) mice compared to WT mice with reduced expressions of
HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM
groups and further increased in Nrf2(-/-) groups. In vitro, given exogenous
TGF-?1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with
down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with
Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT,
respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of
Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the
protection of activating Nrf2 against EMT. In conclusion, activating Nrf2
antioxidant pathway suppresses EMT during PF via inhibiting the abnormal
expression of Numb. These findings provide insight into PF pathogenesis and a
basis for novel treatment approaches.
|*Epithelial-Mesenchymal Transition
[MESH]
|Animals
[MESH]
|Antioxidants/*metabolism
[MESH]
|Bleomycin
[MESH]
|Cell Line
[MESH]
|Disease Models, Animal
[MESH]
|Down-Regulation/drug effects
[MESH]
|Gene Silencing/drug effects
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins/*metabolism
[MESH]
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