Institute of Molecular and Cell Biology, A*STAR, Singapore, 138672, Singapore.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Nat Commun. 2019 Sep 25;10(1):4349. doi: 10.1038/s41467-019-12241-2.
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.
治疗肌层浸润性膀胱癌仍然是一个主要的临床挑战。异常的 HGF/c-MET 上调和激活在膀胱癌中经常观察到，与癌症的进展和侵袭相关。然而，HGF/c-MET 介导的膀胱癌侵袭的机制尚不清楚。作为负反馈回路的一部分，SMAD7 与 SMURF2 结合，靶向 TGFβ 受体进行降解。在这些条件下，SMAD7 通过破坏 SMURF2 内的分子内相互作用，充当 SMURF2 的激动剂。我们证明 HGF 通过 c-SRC 介导的 SMURF2 磷酸化刺激 TGFβ 信号通路，导致 SMAD7 结合丧失和增强的 SMURF2 C2-HECT 相互作用，抑制 SMURF2 并增强 TGFβ 受体稳定性。HGF 对 TGFβ 通路的这种上调导致 TGFβ 介导的 EMT 和侵袭。在体内，我们表明 TGFβ 受体抑制可防止膀胱癌侵袭。此外，我们为联合使用 TGFβ 和 MEK 抑制剂治疗高级别非肌肉浸润性膀胱癌提供了合理的依据。
