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C-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

ABSTRACT: c-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

PROVIDER: PRJNA413704 | ENA |

REPOSITORIES: ENA

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c-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

Project description:Aberrant c-Met activation and upregulation of its cognate ligand HGF are frequently observed in bladder cancer and have been shown to regulate downstream pathways involved in proliferation, motility, and invasion. The precise mechanism underlying HGF/c-MET mediated invasion in bladder cancer is partly addressed by this microarray dataset. HGF activates the canonical TGFb signaling pathway to enhance epithelial mesenchymal transition and bladder carcinoma invasion.

2019-08-23 | GSE104740 | GEO

c-Met activation leads to the establishment of a TGFβ receptor regulatory network required for bladder cancer invasion

Project description: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 precise mechanisms underlying HGF/c-MET mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to the E3 ligase SMURF2 targeting the TGFβ receptor for degradation. Under these conditions SMAD7 acts as an agonist disrupting the intermolecular interactions within SMURF2, permitting SMURF2 activation. We demonstrate that HGF stimulates TGFβ signaling by inducing c-SRC mediated phosphorylation of SMURF2 at two tyrosine residues impeding SMAD7 binding and enhancing SMURF2 C2-HECT domain interaction, resulting in SMURF2 inhibition and TGFβ receptor stabilization. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. Using biologically relevant orthotopic mouse models we show that inhibition of TGFβ signaling completely prevents HGF induced bladder cancer invasion. Furthermore, we make a rationale for the use of TGFβ receptor and MEK inhibitors in the treatment of high grade non-muscle-invasive bladder cancers or early stage muscle invasive bladder cancers.

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Novel functional analysis of MET exon 14 skipping alteration in driving cancer invasion and metastatic dissemination

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

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Establishment and characterization of CRISPR/Cas9-mediated Merlin/NF2 knockout human mesothelial cell line Met-5A

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