Title:HMGA2 Modulates the TGFβ/Smad, TGFβ/ERK and Notch Signaling Pathways in Human Lens Epithelial-Mesenchymal Transition
Volume: 18
Issue: 2
关键词:
高迁移率族蛋白A2（HMGA2）、上皮间质转化（EMT）、晶状体上皮细胞（LEC）、TGF-β信号传导、Notch信号传导。
摘要: Background and Objective: Multiple signaling pathways coordinately
promote epithelial-mesenchymal transition (EMT) in lens epithelial cells (LECs), where
transforming growth factor beta (TGFβ)-mediated signaling plays a central role. But the
mechanism of crosstalk among these pathways remains obscure. The objective of this
study is to investigate the regulatory effect of the high mobility group protein A2
(HMGA2) on the signaling pathways in lens fibrosis.
Methods: The human anterior capsulorhexis specimens were collected. The human
SRA01/04 LEC line was cultured and treated with recombinant human TGFβ2 (5ng/ml).
For inhibition of signaling pathways, a selective inhibitor SB431542, U0126 or DAPT
was added to LECs respectively. The specific small interfering RNA (siRNA) were
transfected to LECs for gene silence. The mRNAs expressions were measured by realtime
PCR and the proteins expressions were determined by western blot and
immunofluorescent staining.
Results: HMGA2 and EMT markers α-smooth muscle actin (SMA), fibronectin (FN) and
collagen type I (Col I) were overexpressed in human ASC specimens and TGFβ2
stimulated EMT in LECs. While blockage of EMT by a selective inhibitor of TGFβ/Smad,
TGFβ/extracellular signal-regulated kinase (ERK) or Notch signaling pathway could
significantly inhibited HMGA2 protein expression. And silence of HMGA2 by siRNA
could significantly inhibit TGFβ2 induced expression of EMT markers including FN, Col I,
collagen type IV (Col IV), key transcription factors Snail and Slug, and remarkably
upregulate the epithelial markers E-cadherin and tight junction protein (ZO-1). In
addition, silence of HMGA2 gene could abrogate TGFβ2 induced phosphorylation of
Smad2, Smad3 as well as ERK1/2. Blockage of HMGA2 could also inhibit the
upregulation of Jagged1, Notch2, and Notch3 induced by TGFβ2.
Conclusion: This study indicated that HMGA2 functions as a shared effector in TGFβ2-
induced lens fibrosis, modulating the signaling network necessary for EMT in a positive
feedback loop.
