FOXC1-induced non-canonical WNT5A-MMP7 signaling regulates invasiveness in triple-negative breast cancer.
FOXC1-induced non-canonical WNT5A-MMP7 signaling regulates invasiveness in triple-negative breast cancer.
复制标题
DOI：
10.1038/s41388-017-0021-2
复制
发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Cui X
中科院分区：
文献类型：
--
作者：
Han B;Zhou B;Qu Y;Gao B;Xu Y;Chung S;Tanaka H;Yang W;Giuliano AE;Cui X
三阴性乳腺癌（TNBC）具有很高的局部复发率和远处转移率，部分原因是其高侵袭性。叉头盒C1 （FOXC1）转录因子已被证明在TNBC中特异性过表达，并与不良临床结果相关。TNBC的高侵袭性是如何由FOXC1及其下游靶点驱动的，目前尚不清楚。在本研究中，通路特异性PCR阵列分析显示，TNBC细胞中WNT5A和基质金属蛋白酶-7 （matrix metalloproteinase-7, MMP7）被FOXC1上调。有趣的是，WNT5A介导了FOXC1对MMP7的上调，WNT5A-MMP7轴对于FOXC1诱导TNBC细胞的体外侵袭至关重要。异种移植模型显示，敲除WNT5A可减弱foxc1过表达TNBC细胞的肺外渗和转移，而过表达MMP7可使其恢复。机制上，FOXC1可以直接结合到WNT5A启动子区域激活其表达。工程dna结合分子介导的染色质免疫沉淀（enChIP），结合质谱，鉴定了foxc1相互作用蛋白，包括一组参与WNT5A转录诱导的异质核核糖核蛋白。最后，我们发现WNT5A激活NF-κB信号，诱导MMP7表达。总的来说，这些数据表明foxc1引发的非典型WNT5A信号机制包括NF-κB和MMP7，这对TNBC细胞侵袭至关重要，从而为开发有效的TNBC治疗方法提供了启示。
Triple-negative breast cancer (TNBC) has high rates of local recurrence and distant metastasis, partially due to its high invasiveness. The Forkhead box C1 (FOXC1) transcription factor has been shown to be specifically overexpressed in TNBC and associated with poor clinical outcome. How TNBC’s high invasiveness is driven by FOXC1 and its downstream targets remains poorly understood. In the present study, pathway-specific PCR array assays revealed that WNT5A and matrix metalloproteinase-7 (MMP7) were upregulated by FOXC1 in TNBC cells. Interestingly, WNT5A mediates the upregulation of MMP7 by FOXC1 and the WNT5A-MMP7 axis is essential for FOXC1-induced invasiveness of TNBC cells in vitro. Xenograft models showed that the lung extravasation and metastasis of FOXC1-overexpressing TNBC cells were attenuated by knocking out WNT5A, but could be restored by MMP7 overexpression. Mechanistically, FOXC1 can bind directly to the WNT5A promoter region to activate its expression. Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP), coupled with mass spectrometry, identified FOXC1-interacting proteins including a group of heterogeneous nuclear ribonucleoproteins involved in WNT5A transcription induction. Finally, we found that WNT5A activates NF-κB signaling to induce MMP7 expression. Collectively, these data demonstrate a FOXC1-elicited non-canonical WNT5A signaling mechanism comprising NF-κB and MMP7 that is essential for TNBC cell invasiveness, thereby providing implications toward developing an effective therapy for TNBC.
登录
查看更多内容
影响因子：
64.5
作者：
Gujral TS;Chan M;Peshkin L;Sorger PK;Kirschner MW;MacBeath G
通讯作者：
MacBeath G
通过激活基质金属蛋白酶7，剪切应力促进软骨肉瘤细胞运动、侵袭和肺部定植
影响因子：
--
作者：
Guan PP;Yu X;Guo JJ;Wang Y;Wang T;Li JY;Konstantopoulos K;Wang ZY;Wang P
通讯作者：
Wang P
影响因子：
11.5
作者：
Hoeflich, Klaus P.;O'Brien, Carol;Lackner, Mark R.
通讯作者：
Lackner, Mark R.
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
8.8
作者：
Han B;Qu Y;Jin Y;Yu Y;Deng N;Wawrowsky K;Zhang X;Li N;Bose S;Wang Q;Sakkiah S;Abrol R;Jensen TW;Berman BP;Tanaka H;Johnson J;Gao B;Hao J;Liu Z;Buttyan R;Ray PS;Hung MC;Giuliano AE;Cui X
通讯作者：
Cui X