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

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Muscle-invasive bladder cancer presents significant treatment challenges.
• Hepatocyte growth factor (HGF) and its receptor c-MET are frequently upregulated in bladder cancer, correlating with progression and invasion.
• The precise mechanisms of HGF/c-MET-driven invasion remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which HGF/c-MET signaling promotes bladder cancer invasion.
• To investigate the interplay between HGF/c-MET and transforming growth factor beta (TGFβ) signaling pathways in bladder cancer.
• To identify potential therapeutic targets for bladder cancer treatment.

Main Methods:

• Investigated the interaction between SMAD7, SMURF2, and the TGFβ receptor.
• Utilized cell-based assays and in vivo models to study HGF-mediated signaling.
• Examined the effects of TGFβ receptor inhibition on bladder cancer invasion.

Main Results:

• HGF induces c-SRC-mediated phosphorylation of SMURF2, disrupting SMAD7 binding and enhancing SMURF2-mediated TGFβ receptor stabilization.
• This leads to increased TGFβ signaling, promoting epithelial-mesenchymal transition (EMT) and invasion.
• In vivo, TGFβ receptor inhibition effectively suppressed bladder cancer invasion.

Conclusions:

• HGF/c-MET signaling promotes bladder cancer invasion through the upregulation of TGFβ signaling.
• Targeting TGFβ receptors represents a viable strategy to inhibit bladder cancer invasion.
• Combinatorial therapy with TGFβ and MEK inhibitors is proposed for high-grade non-muscle-invasive bladder cancers.