期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-12241-2
关键词
-
资金
- Institute of Molecular and Cell Biology
- Joint Council Office Development Programme [1234e00018]
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centers of Excellence initiative
- Singapore Ministry of Education under its Ministry of Education Academic Research Fund Tier 1 grants [T1-2013, T1-2014]
- European Union [786880]
- Cancer Genomics Centre Netherlands
- Agency for Science, Technology and Research (A* STAR)
- Marie Curie Actions (MSCA) [786880] Funding Source: Marie Curie Actions (MSCA)
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 TGF beta receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGF beta signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGF beta receptor stabilisation. This upregulation of the TGF beta pathway by HGF leads to TGF beta-mediated EMT and invasion. In vivo we show that TGF beta receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGF beta and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据