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Hsp90β promotes aggressive vasculogenic mimicry via epithelial–mesenchymal transition in hepatocellular carcinoma

Oncogenevolume 38pages228243 (2019) | Download Citation

Abstract

Hepatocellular carcinoma (HCC) is a typical hypervascular solid tumor. Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. Hsp90β promotes endothelial cell-dependent angiogenesis in HCC. However, the relationship between Hsp90β and VM formation is unclear. In this study, we found that Hsp90β is positively correlated with VM and EMT marker proteins in HCC tissues and promotes tube formation, cell migration, and invasion in vitro. Hsp90β interacts with Twist1 and promotes its deubiquitination and stabilization to nuclear translocation and enhances the VE-cadherin promoter activity. Results of in vitro analysis indicate that Hsp90β enhances the tumor VM in tumor-burdened mice, and the Hsp90 inhibitor NVP-BEP800 suppresses VM formation by releasing Hsp90β and Twist1 interaction. This study provides a potential antitumor therapy for inhibiting VM by targeting Hsp90β in HCC.

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Additional information

These authors contributed equally: Jing Meng, Shuang Chen

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant nos. 81572838, 81402973 and 81703581), Tianjin Natural Science and Technology Fund (Grant no. 15JCYBJC26400), Tianjin Science and Technology Project (grant no.15PTGCCX00140), and the National Science and Technology Major Project (grant no.2017ZX09306007).

Author contributions

JM, TS and CY designed experiments. JM, SC, YYL, JXH, and XRW performed the research. WLZ and WFG. carried out the bioinformatics analysis. QT, QZ, and HJL performed the animal experiment. JM and YRL performed the pathological analysis. JM, HGZ constructed the cloning vector. JM and TS wrote the manuscript, with contributions from all other authors.

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    Affiliations

    1. State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China

      • Jing Meng
      • , Yue-yang Lei
      • , Jing-xia Han
      • , Wei-long Zhong
      • , Wan-feng Gao
      • , Qiang Zhang
      • , Qiang Tan
      • , Hong-gang Zhou
      • , Tao Sun
      •  & Cheng Yang
    2. Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China

      • Shuang Chen
      • , Yan-rong Liu
      • , Qiang Tan
      • , Hui-juan Liu
      • , Tao Sun
      •  & Cheng Yang
    3. College of Life Science, Nankai University, Tianjin, China

      • Xiao-rui Wang
      •  & Hui-juan Liu

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    The authors declare that they have no conflict of interest.

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    Correspondence to Tao Sun or Cheng Yang.

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    https://doi.org/10.1038/s41388-018-0428-4