Zhang X, Zhang L, Du Y, Zheng H, Zhang P, Sun Y, Wang Y, Chen J, Ding P, Wang N, Yang C, Huang T, Yao X, Qiao Q, Gu H, Cai G, Cai S, Zhou X, Hu W
Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Collaborative Innovation Center of Cancer Medicine, Shanghai Medical College, Fudan University; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Department of Colorectal Surgery, Shanghai Medical College, Fudan University, Shanghai, China.
Oncogene. 2017 Feb 9;36(6):807-819. doi: 10.1038/onc.2016.249. Epub 2016 Jul 11.
Epithelial-mesenchymal transition (EMT) is a critical event in metastasis of colorectal cancer (CRC). Rho/ROCKs signaling has a pivotal role in orchestrating actin cytoskeleton, leading to EMT and cancer invasion. However, the underlying mechanisms for ROCKs activation are not fully understood. Here, we identified FOXM1D, a novel isoform of Forkhead box M1 (FOXM1) that has a pivotal role in ROCKs activation by directly interacting with coiled-coil region of ROCK2. FOXM1D overexpression significantly polymerizes actin assembly and impairs E-cadherin expression, resulting in EMT and metastasis in xenograft mouse model and knockdown of FOXM1D has the opposite effect. Moreover, a high FOXM1D level correlates closely with clinical CRC metastasis. FOXM1D-induced ROCKs activation could be abrogated by the ROCKs inhibitors Y-27632 and fasudil. These observations indicate that the FOXM1D-ROCK2 interaction is crucial for Rho/ROCKs signaling and provide novel insight into actin cytoskeleton regulation and therapeutic potential for CRC metastasis.
上皮-间质转化（EMT）是结直肠癌（CRC）转移过程中的关键事件。Rho/ROCK信号通路在调控肌动蛋白细胞骨架、导致EMT和癌症侵袭方面起着关键作用。然而，ROCK激活的潜在机制尚未完全明确。在此，我们鉴定出FOXM1D，它是叉头框M1（FOXM1）的一种新型异构体，通过与ROCK2的卷曲螺旋区域直接相互作用，在ROCK激活中起关键作用。FOXM1D的过表达显著促进肌动蛋白组装聚合，并损害E-钙黏蛋白的表达，导致异种移植小鼠模型中的EMT和转移，而敲低FOXM1D则产生相反的效果。此外，FOXM1D的高表达水平与临床CRC转移密切相关。ROCK抑制剂Y-27632和法舒地尔可消除FOXM1D诱导的ROCK激活。这些观察结果表明，FOXM1D-ROCK2相互作用对Rho/ROCK信号通路至关重要，并为肌动蛋白细胞骨架调控及CRC转移的治疗潜力提供了新的见解。
