Ten Dijke P
TRAF4 inhibits bladder cancer progression by promoting BMP/SMAD signalling pathway
Bladder cancer is a highly prevalent cancer with poor clinical outcomes, especially in advanced stages of progression when the cancer starts invading the bladder muscle (1). Epithelial-to-mesenchymal transition (EMT) has been implicated in bladder cancer progression and metastasis. EMT is a dynamic process in which epithelial cells lose their cell–cell contacts and apical–basal polarity and gain mesenchymal traits with increased migration and invasion abilities (2, 3). Cells lose the expression of epithelial markers such as E-cadherin and gain the expression of mesenchymal markers such as N-cadherin (4). This process is orchestrated by EMT-inducing transcription factors, including SNAIL and SLUG (5, 6). TGFβ signaling pathway is known to stimulate EMT (7).
Readc-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression
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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