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TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-κB

Oncogene volume 29, pages 3619–3629 (2010)Cite this article

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Abstract

Aneurysmal bone cyst (ABC) is an aggressive, pediatric bone tumor characterized by extensive destruction of the surrounding bone. Although first described over 60 years ago, its molecular etiology remains poorly understood. Recent work revealed that ABCs harbor translocation of TRE17/USP6, leading to its transcriptional upregulation. TRE17 encodes a ubiquitin-specific protease (USP), and a TBC domain that mediates binding to the Arf6 GTPase. However, the mechanisms by which TRE17 overexpression contributes to tumor pathogenesis, and the role of its USP and TBC domains, are unknown. ABCs are characterized by osteolysis, inflammatory recruitment and extensive vascularization, the processes in which matrix proteases have a prominent role. This led us to explore whether TRE17 regulates the production of matrix metalloproteinases (MMPs). In this study we show that TRE17 is sufficient to induce expression of MMP-9 and MMP-10, in a manner requiring its USP activity, but not its ability to bind Arf6. TRE17 induces transcription of MMP-9 through activation of nuclear factor-κB (NF-κB), mediated in part by the GTPase RhoA and its effector kinase, ROCK. Furthermore, xenograft studies show that TRE17 induces formation of tumors that reproduce multiple features of ABC, including a high degree of vascularization, with an essential role for the USP domain. In sum, these studies reveal that TRE17 is sufficient to initiate tumorigenesis, identify MMPs as novel TRE17 effectors that likely contribute to ABC pathogenesis and define the underlying signaling mechanism of their induction.

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Acknowledgements

This work was supported by the NIH Grants CA081415 (MMC), DK58044 (GAB) and P30 AR050950 (Penn Center for Musculoskeletal Disorders). Additional support was from the Mayo Foundation CR20 Program (AMO), the Pennsylvania Muscle Institute Pilot Project Grant (MMC) and the Pennsylvania Department of Health (MMC), which specifically disclaims responsibility for any analysis, interpretations or conclusions. We thank Yvette Liu for invaluable assistance with bioluminescence imaging.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Y Ye, L M Pringle, A W Lau, D N Riquelme & M M Chou

  2. Division of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    H Wang & G A Blobel

  3. Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    T Jiang

  4. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Lev

  5. Edinburgh Cancer Research Center, University of Edinburgh, Edinburgh, UK

    A Welman

  6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    A M Oliveira

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Ye, Y., Pringle, L., Lau, A. et al. TRE17/USP6 oncogene translocated in aneurysmal bone cyst induces matrix metalloproteinase production via activation of NF-κB. Oncogene 29, 3619–3629 (2010). https://doi.org/10.1038/onc.2010.116

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