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Hypoxia induces the activation of hepatic stellate cells through the PVT1-miR-152-ATG14 signaling pathway

Abstract

Increasing studies have indicated that hypoxia serves as a pivotal microenvironmental factor that facilitates activation of hepatic stellate cells (HSCs). However, the mechanism by which hypoxia activates HSCs is not clear. Here, we demonstrated that plasmacytoma variant translocation 1 (PVT1) and autophagy were overexpressed in liver fibrotic specimens. In primary mouse HSCs, both PVT1 and autophagy were induced by hypoxia. Further study showed that hypoxia-induced autophagy depended on expression of PVT1 and miR-152 in HSCs. Luciferase reporter assay indicated that autophagy-related gene 14 (ATG14) was a direct target of miR-152. In addition, inhibition of autophagy by 3‐methyladenine and Beclin-1 siRNA impeded activation of HSCs cultured in 1% O2. Taken together, autophagy induction via the PVT1-miR-152-ATG14 signaling pathway contributes to activation of HSCs under hypoxia condition.

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Acknowledgements

The project was supported by the Shanghai Municipal Natural Science Foundation (Grant No. 17ZR1426100), the National Natural Science Foundation of China (Grant Nos. 81970527/H0317, 81500458/H0317, 81873576/H0317, 81000176/H0317), Zhejiang Provincial Natural Science Foundation of China (Grant No. LY19H030005), Wenzhou Municipal Science and technology Bureau (Grant No. Y20180138), the Key Project of the Science & Technology Development Fund of Nanjing Medical University (Grant No. 2016NJMUZD092), and Science & Technology Commission of Shanghai Songjiang (Grant No. 16SJGG38).

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Correspondence to Jianjian Zheng or Ping Xu.

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Yu, F., Dong, B., Dong, P. et al. Hypoxia induces the activation of hepatic stellate cells through the PVT1-miR-152-ATG14 signaling pathway. Mol Cell Biochem 465, 115–123 (2020). https://doi.org/10.1007/s11010-019-03672-y

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Keywords

  • Hepatic stellate cell
  • Plasmacytoma variant translocation 1 (PVT1)
  • microRNA-152
  • Autophagy
  • Hypoxia