ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA
ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA
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DOI：
10.1158/0008-5472.can-16-3141
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发表时间：
2017-08-01
期刊：
影响因子：
11.2
通讯作者：
Yang, Chengfeng
中科院分区：
文献类型：
--
作者：
Humphries, Brock;Wang, Zhishan;Yang, Chengfeng
在癌细胞中激活的Rho GTP酶驱动增殖、迁移和转移。因此，RhoGAP蛋白，负调节Rho GTP酶，通常被认为是作为肿瘤抑制剂。在这里，这一预期受到ARHGAP 18的表征的挑战，ARHGAP 18是一种RhoGAP家族成员，在高度迁移的三阴性乳腺癌（TNBC）细胞中选择性过表达。在人类乳腺肿瘤中，较高的ARHGAP 18水平与较差的总生存期、无复发生存期和无转移生存期相关。在TNBC细胞中，ARHGAP 18缺失增加了RhoA活化，但降低了生长、迁移和转移能力。机制研究显示，ARHGAP 18水平受miR-200 b控制，其强制表达足以激活RhoA，增强粘着斑和肌动蛋白应力纤维的形成，并减少迁移和转移。在miR 200 b稳定表达的地方，ARHGAP 18的强制升高降低了RhoA活性，但增加了细胞迁移。Rho效应激酶ROCK的药理学抑制阻断了RhoA信号传导并逆转了miR-200 b对细胞迁移的抑制作用。最后，ARHGAP 18过表达或ROCK抑制足以克服miR-200 b的转移阻断。总之，这些结果定义了致癌ARHGAP 18和肿瘤抑制性miR-200 b在确定TNBC细胞迁移和转移能力中的相反作用。(C)2017年AACR。
Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARHGAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess. (C) 2017 AACR.