c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression
| Autor: | Pieter Johan Adam Eichhorn, Wen Jing Sim, Peter ten Dijke, Tuan Zea Tan, Alan Prem Kumar, Dilraj Lama, Camelia Radulescu, Mathieu Rouanne, Eytan Domany, Hsien Chun Ng, Chandra S. Verma, Hong Koo Ha, Patrick Jaynes, Sarah Kit Leng Lui, Jean Paul Thiery, Dennis Kappei, Azad Saei, Prasanna Vasudevan Iyengar, Lior Haviv-Shapira |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Ubiquitylation Molecular biology General Physics and Astronomy Kaplan-Meier Estimate chemistry.chemical_compound 0302 clinical medicine Receptor lcsh:Science Cancer Hepatocyte growth factor Mice Inbred BALB C Multidisciplinary biology Chemistry Bladder cancer Proto-Oncogene Proteins c-met Downregulation and upregulation 3. Good health Ubiquitin ligase Gene Expression Regulation Neoplastic 030220 oncology & carcinogenesis Benzamides Disease Progression Quinolines Female Proto-oncogene tyrosine-protein kinase Src medicine.drug Epithelial-Mesenchymal Transition C-Met Science Mice Nude Cancer research Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Cell Line Tumor medicine Animals Humans Author Correction Biology Gene Expression Profiling Diphenylamine General Chemistry medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Urinary Bladder Neoplasms biology.protein Pyrazoles lcsh:Q MAPK/ERK pathway Receptors Transforming Growth Factor beta |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-19 (2019) PubMed Central DOAJ-Articles Datacite UnpayWall ORCID Microsoft Academic Graph Nature Communications Nature Communications, 10 |
| Popis: | 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. HGF/c-MET upregulation is frequent in bladder cancer. Here, the authors show that HGF induces EMT and invasion by stabilising TGFβ receptor through inhibition of the SMURF2 ligase, and the combined blockade of MAPK and TGFβ pathways suppresses HGF-mediated bladder cancer progression. |
| Databáze: | OpenAIRE |
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