PMID- 28699703
OWN - NLM
STAT- MEDLINE
DCOM- 20180711
LR  - 20201209
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Print)
IS  - 1582-1838 (Linking)
VI  - 21
IP  - 12
DP  - 2017 Dec
TI  - A positive feedback loop promotes HIF-1alpha stability through miR-210-mediated 
      suppression of RUNX3 in paraquat-induced EMT.
PG  - 3529-3539
LID - 10.1111/jcmm.13264 [doi]
AB  - Irreversible pulmonary fibrosis induced by paraquat (PQ) poisoning is the major 
      cause of death in patients with PQ poisoning. The epithelial-mesenchymal 
      transition (EMT) is postulated to be one of the main mechanisms of pulmonary 
      fibrosis. Here, we investigated the role of miR-210 in PQ-induced EMT and its 
      relationship with hypoxia-inducible factor-1alpha (HIF-1alpha). Western blotting, 
      immunofluorescence, immunoprecipitation and other methods were used in this 
      study. We found that miR-210 expression was significantly increased after PQ 
      poisoning, and it may be regulated by HIF-1alpha. Overexpression of miR-210 further 
      increased the HIF-1alpha protein level and promoted EMT. Moreover, miR-210 knock-down 
      reduced the HIF-1alpha protein level and decreased the degree of EMT. Runt-related 
      transcription factor-3 (RUNX3), a direct target of miR-210, was inhibited by 
      miR-210 in response to PQ poisoning. RUNX3 increased the hydroxylation ability of 
      prolyl hydroxylase domain-containing protein 2 (PHD2), a key enzyme that promotes 
      HIF-1alpha degradation. PHD2 immunoprecipitated with RUNX3 and its level changed 
      similarly to that of RUNX3. The expression of the HIF-1alpha protein was 
      significantly reduced when RUNX3 was overexpressed. HIF-1alpha protein levels were 
      markedly increased when RUNX3 was silenced. Based on these results, a positive 
      feedback loop may exist between miR-210 and HIF-1alpha. The mechanism may function 
      through miR-210-mediated repression of RUNX3, which further decreases the 
      hydroxylation activity of PHD2, enhances the stability of HIF-1alpha, and promotes 
      PQ-induced EMT, aggravating the progression of pulmonary fibrosis. This study 
      further elucidates the mechanism of PQ-induced pulmonary fibrosis and may provide 
      a new perspective for the future development of therapies.
CI  - (c) 2017 The Authors. Journal of Cellular and Molecular Medicine published by John 
      Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
FAU - Zhu, Yong
AU  - Zhu Y
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Wang, Jinfeng
AU  - Wang J
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Meng, Xiaoxiao
AU  - Meng X
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Xie, Hui
AU  - Xie H
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Tan, Jiuting
AU  - Tan J
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Guo, Xinkun
AU  - Guo X
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Han, Peng
AU  - Han P
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
FAU - Wang, Ruilan
AU  - Wang R
AUID- ORCID: 0000-0001-9555-2649
AD  - Department of Critical Care Medicine, Shanghai General Hospital, Shanghai 
      Jiaotong University, School of Medicine, Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20170712
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Core Binding Factor Alpha 3 Subunit)
RN  - 0 (Hif1a protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (MIRN210 microRNA, rat)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Small Interfering)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Egln1 protein, rat)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - PLG39H7695 (Paraquat)
SB  - IM
MH  - A549 Cells
MH  - Animals
MH  - Cell Line
MH  - Core Binding Factor Alpha 3 Subunit/antagonists & inhibitors/*genetics/metabolism
MH  - Epithelial-Mesenchymal Transition/*drug effects
MH  - *Feedback, Physiological
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/metabolism
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Male
MH  - MicroRNAs/*genetics/metabolism
MH  - Paraquat/*poisoning
MH  - Procollagen-Proline Dioxygenase/genetics/metabolism
MH  - Protein Stability
MH  - Proteolysis
MH  - Pulmonary Fibrosis/chemically induced/*genetics/metabolism/pathology
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
PMC - PMC5706527
OTO - NOTNLM
OT  - MicroRNA-210
OT  - epithelial-mesenchymal transition
OT  - hypoxia-inducible factor-1alpha
OT  - paraquat poisoning
OT  - pulmonary fibrosis
OT  - runt-related transcription factor-3
EDAT- 2017/07/13 06:00
MHDA- 2018/07/12 06:00
PMCR- 2017/12/01
CRDT- 2017/07/13 06:00
PHST- 2017/01/07 00:00 [received]
PHST- 2017/04/28 00:00 [accepted]
PHST- 2017/07/13 06:00 [pubmed]
PHST- 2018/07/12 06:00 [medline]
PHST- 2017/07/13 06:00 [entrez]
PHST- 2017/12/01 00:00 [pmc-release]
AID - JCMM13264 [pii]
AID - 10.1111/jcmm.13264 [doi]
PST - ppublish
SO  - J Cell Mol Med. 2017 Dec;21(12):3529-3539. doi: 10.1111/jcmm.13264. Epub 2017 Jul 
      12.