Dvl2 依赖性激活 Daam1 和 RhoA 调节 Wnt5a 诱导的乳腺癌细胞迁移。

Dvl2-dependent activation of Daam1 and RhoA regulates Wnt5a-induced breast cancer cell migration.

机构信息

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

出版信息

PLoS One. 2012;7(5):e37823. doi: 10.1371/journal.pone.0037823. Epub 2012 May 24.

BACKGROUND

The Dishevelled (Dvl) and Dishevelled-associated activator of morphogenesis 1 (Daam1) pathway triggered by Wnt5a regulates cellular polarity during development and tissue homoeostasis. However, Wnt5a signaling in breast cancer progression remains poorly defined.

METHODOLOGY/PRINCIPAL FINDINGS: We showed here that Wnt5a activated Dvl2, Daam1 and RhoA, and promoted migration of breast cancer cells, which was, however, abolished by Secreted Frizzled-related protein 2 (sFRP2) pretreatment. Dominant negative Dvl2 mutants or Dvl2 siRNA significantly decreased Wnt5a-induced Daam1/RhoA activation and cell migration. Ectopic expression of N-Daam1, a dominant negative mutant, or Daam1 siRNA remarkably inhibited Wnt5a-induced RhoA activation, stress fiber formation and cell migration. Ectopic expression of dominant negative RhoA (N19) or C3 exoenzyme transferase, a Rho inhibitor, decreased Wnt5a-induced stress fiber formation and cell migration.

CONCLUSIONS/SIGNIFICANCE: Taken together, we demonstrated for the first time that Wnt5a promotes breast cancer cell migration via Dvl2/Daam1/RhoA.

背景

Wnt5a 触发的蓬乱蛋白（Dvl）和蓬乱蛋白相关形态发生激活蛋白 1（Daam1）通路在发育和组织稳态过程中调节细胞极性。然而，Wnt5a 信号在乳腺癌进展中的作用仍不清楚。

方法/主要发现：我们在这里表明，Wnt5a 激活了 Dvl2、Daam1 和 RhoA，并促进了乳腺癌细胞的迁移，但这一过程被分泌卷曲相关蛋白 2（sFRP2）预处理所阻断。显性负 Dvl2 突变体或 Dvl2 siRNA 显著降低了 Wnt5a 诱导的 Daam1/RhoA 激活和细胞迁移。N-Daam1 的异位表达，一种显性负突变体，或 Daam1 siRNA 显著抑制了 Wnt5a 诱导的 RhoA 激活、应力纤维形成和细胞迁移。显性负 RhoA（N19）或 Rho 抑制剂 C3 外切酶转移酶的异位表达降低了 Wnt5a 诱导的应力纤维形成和细胞迁移。

结论/意义：综上所述，我们首次证明 Wnt5a 通过 Dvl2/Daam1/RhoA 促进乳腺癌细胞迁移。