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Hypoxia-induced microRNA-191 contributes to hepatic ischemia/reperfusion injury through the ZONAB/Cyclin D1 axis

Cell Death & Differentiationvolume 26pages291305 (2019) | Download Citation


Hepatic ischemia/reperfusion injury (IRI) is a common cause of morbidity and mortality in liver transplantation settings and involves severe cell death and inflammatory responses. MicroRNA-191 has recently been reported to be abnormally expressed in hepatocellular carcinoma and other liver diseases in the regulation of important cellular processes. However, little is known about its function and molecular mechanism in IRI. Here, we demonstrate that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion (H/R) and in liver tissue during IRI in mice. The activation of miR-191 under hypoxic conditions is mediated by hypoxia-inducible factor-1α (HIF1α) binding to its promoter region. Global miR-191 KO mice were constructed by CRISPR/Cas9 system, and we found that miR-191 deficiency markedly reduces liver tissue damage, cell inflammatory responses and cell death in a mouse hepatic IRI model. Under the H/R condition, miR-191 overexpression promotes G0/G1 cell cycle arrest and cell apoptosis, but inhibition of miR-191 facilitates cell cycle progression and decreases cell death. Mechanistically, upon induction by hypoxia or ischemia, miR-191 suppresses expression of ZO-1-associated Y-box factor (ZONAB) and its downstream factor Cyclin D1, consequently resulting in cell death and tissue injury. Moreover, the effects of miR-191 on cell cycle arrest and cell apoptosis are abrogated by ZONAB overexpression, and vice versa. Taken together, our results indicate an important role of the HIF1α/miR-191/ZONAB signaling pathway in hepatic IRI and suggest miR-191 as a novel therapeutic target for the treatment of liver IRI.

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These authors contributed equally: Wenming Pan, Lin Wang, Xiao-Fei Zhang, Hongji Zhang.

Edited by R. De Maria.


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This study was supported by grants from the National Natural Science Foundation of China (nos. 81070355 to JXZ, 81570570 to HW, 81470375 to X-DZ and 31501148 to R-LD). We also appreciate Jinhui Zhang (Laboratory of general surgery, Union Hospital, Wuhan, China) for providing assistance with RT-PCR.

Author contributions

W-MP, LW, X-FZ and H-JZ performed and analyzed experiments. HW, J-XZ, W-MP, X-FZ and H-JZ performed statistical analyses. X-DZ and R-LD provided plasmids and reagents. G-LW and PX helped to construct plasmids and stable cell lines. Y-WZ and PH performed histopathologic analysis. HW, R-LD, J-XZ and X-DZ designed the overall research and directed the work. HW, R-LD and X-FZ wrote the manuscript. All authors discussed the results, reviewed and approved the final manuscript.

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Author notes


    1. Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, 430022, Wuhan, P.R. China

      • Wenming Pan
      • , Hongji Zhang
      • , Jinxiang Zhang
      • , Peng Xu
      • , Yunwei Zhang
      •  & Ping Hu
    2. Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, 430022, Wuhan, P.R. China

      • Lin Wang
    3. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, 430072, Wuhan, P.R. China

      • Xiao-Fei Zhang
      • , Xiao-Dong Zhang
      •  & Run-Lei Du
    4. Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, P.R. China

      • Xiao-Fei Zhang
    5. Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, 430022, Wuhan, P.R. China

      • Guoliang Wang
    6. Department of Medical Genetics, Basic school of Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, 430030, Wuhan, P.R. China

      • Hui Wang


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    Correspondence to Run-Lei Du or Hui Wang.

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