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Adenoviral delivery of VHL suppresses bone sarcoma cell growth through inhibition of Wnt/β-catenin signaling

Cancer Gene Therapy volume 26, pages 83–93 (2019)Cite this article

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Abstract

The VHL tumor suppressor gene is frequently inactivated in several human tumors, including bone sarcomas. We previously identified that reduced expression of VHL protein is implicated in sarcomagenesis. However, the underlying biological functions of restored VHL protein expression have not been clearly elucidated in bone sarcomas. Here we initially constructed a recombinant adenovirus 5-VHL vector (Ad5-VHL) and evaluated its expression in bone sarcomas, and antitumor activity in vitro and in vivo. We found that the adenovirus-mediated increase of VHL significantly suppresses bone sarcoma cell growth, attributed to induction of apoptosis mediated by increased caspase-3 activity and modulated Bcl-2 protein family. This suppression effect involves inhibition of Wnt/β-catenin signaling and upregulation of GSK-3β. Moreover, Ad5-VHL showed a dramatic antitumor effect on a chondrosarcoma xenograft model. These findings establish that Ad5-VHL suppresses bone sarcoma cell growth by inhibiting Wnt/β-catenin signaling, and may be a novel target for gene-based therapy of bone sarcomas.

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Acknowledgements

This work was supported by grants from the National Natural Sciences Foundation of China (81102037), and was also supported by grants from TianJin Youth Medicine Talents Plan.

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Authors and Affiliations

  1. Department of Spinal Surgery, Tianjin Hospital, 406 Jiefang South Road, Tianjin, 300211, P.R. China

    Changbao Chen & Xinlong Ma

  2. Department of Orthopedics Institute, Tianjin Hospital, 406 Jiefang South Road, Tianjin, 300211, P.R. China

    Aixian Tian

  3. Department of Medical Laboratory, Tianjin Medical University Cancer Institute and Hospital, Huan-Hu-Xi Road, Ti-Yuan-Bei, Tianjin, 300060, P.R. China

    Meng Zhao

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  1. Changbao Chen
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Correspondence to Xinlong Ma.

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Chen, C., Tian, A., Zhao, M. et al. Adenoviral delivery of VHL suppresses bone sarcoma cell growth through inhibition of Wnt/β-catenin signaling. Cancer Gene Ther 26, 83–93 (2019). https://doi.org/10.1038/s41417-018-0041-2

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