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    c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression

    78050.pdf (7.268Mb)
    Access Status
    Open access
    Authors
    Sim, W.J.
    Iyengar, P.V.
    Lama, D.
    Lui, S.K.L.
    Ng, H.C.
    Haviv-Shapira, L.
    Domany, E.
    Kappei, D.
    Tan, T.Z.
    Saie, A.
    Jaynes, P.W.
    Verma, C.S.
    Kumar, A.P.
    Rouanne, M.
    Ha, H.K.
    Radulescu, C.
    ten Dijke, P.
    Eichhorn, Pieter
    Thiery, J.P.
    Date
    2019
    Type
    Journal Article
    
    Metadata
    Show full item record
    Citation
    Sim, W.J. and Iyengar, P.V. and Lama, D. and Lui, S.K.L. and Ng, H.C. and Haviv-Shapira, L. and Domany, E. et al. 2019. c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression. Nature Communications. 10 (1): ARTN 4349.
    Source Title
    Nature Communications
    DOI
    10.1038/s41467-019-12241-2
    ISSN
    2041-1723
    Faculty
    Faculty of Health Sciences
    School
    School of Pharmacy and Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/77888
    Collection
    • Curtin Research Publications
    Abstract

    Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.

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