Effects and mechanism of dehydroepiandrosterone on epithelial-mesenchymal transition in bronchial epithelial cells.
BACKGROUND
Chronic persistent asthma is characterized by airway remodeling, in which epithelial-mesenchymal transition (EMT) may play a significant role. Dehydroepiandrosterone (DHEA), a steroid hormone and testosterone analog, is considered as an important immunomodulating hormone. However, its role in EMT remains unclear. We sought to investigate whether transforming growth factor-β1 (TGF-β1) stimulates human bronchial epithelial cells (16HBE-14o) to undergo EMT, and whether this transition can be abrogated by DHEA.


METHODS
The 16HBE-14o cells were stimulated with 5 ng/ml TGF-β1 for 3 days to induce EMT, with or without DHEA pretreatment, and assayed for epithelial or mesenchymal markers using Western Blot. The involvement of phosphoinositide 3-kinase (PI3K) -mediated signaling pathway was also evaluated, the epithelial cells were also incubated with pharmacological approaches (agonists and antagonists of Akt, LY294002 or IGF-1) or flutamide, the antagonist of androgen receptor. Results were analyzed using nonparametric statistical tests.


RESULTS
Our data demonstrate that treatment of 16HBE-14o cells with TGF-β1 for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E-cadherin, and acquisition of a-smooth muscle actin (a-SMA). Pretreatment of 16HBE-14o cells with DHEA preserved the epithelial-like morphology, restored the expression of E-cadherin, and abolished the activation of a-SMA, and this effect is a PI3K-dependent mechanism.


CONCLUSIONS
Our results indicate that TGF-β1 induces EMT in a PI3K-dependent manner in 16HBE-14o cells. DHEA inhibits the bronchial epithelial to mesenchymal transition via the inhibition of PI3K/Akt-dependent signal pathway stimulated by TGF-β1. Therefore, DHEA may be a useful therapy for asthma.
1Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha City, Hunan Province, China.
Li
L
Xu
Xudong
X
Xiang
Xiaoying
X
Ji
Wenjing
W
Wang
Min
M
Luo
Shuangling
S
Luo
Keng
K
Li
Subo
S
Gong
Shaokun
S
Liu
Libing
L
Ma
Ping
P
Chen
Jinxiu
J
Li
D001980:Bronchi / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011944:Receptors, Androgen / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D011944:Receptors, Androgen; D053773:Transforming Growth Factor beta1; D003687:Dehydroepiandrosterone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt