ROR2 receptor promotes the migration of osteosarcoma cells in response to Wnt5a.
ROR2 receptor promotes the migration of osteosarcoma cells in response to Wnt5a.
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DOI：
10.1186/s12935-017-0482-y
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发表时间：
2017
影响因子：
5.8
通讯作者：
Zhang A
中科院分区：
文献类型：
--
作者：
Dai B;Yan T;Zhang A
我们已经报道了磷脂酰肌醇-3激酶（PI 3 K）/Akt/RhoA信号通路介导Wnt 5a诱导的骨肉瘤细胞迁移。然而，在骨肉瘤转移中，Wnt 5a配体的特异性受体仍然不清楚。伤口愈合测定用于测量用特异性针对ROR 2的shRNA或siRNA或指定构建体转染的骨肉瘤细胞的迁移率。我们用RhoA激活试验检测了骨肉瘤MG-63和U2 OS细胞中RhoA的激活。一组PI 3 K和Akt抑制剂处理骨肉瘤细胞并阻断激酶活性。Western blotting检测Akt的表达和活化。克隆形成试验用于测量ROR 2敲低或ROR 2过表达的骨肉瘤细胞的细胞增殖。Wnt 5a诱导的骨肉瘤细胞迁移在很大程度上被针对ROR 2的shRNA或siRNA特异性消除。RhoA-CA（GFP-RhoA-V14）的过表达能够拯救由ROR 2敲低阻断的Wnt 5a诱导的细胞迁移。Wnt 5a诱导的RhoA激活主要被ROR 2敲低阻断，而被ROR 2过表达升高。此外，我们发现RhoA-siRNA转染或HS-173（PI 3 K α抑制剂），MK-2206（Akt抑制剂），A-674563（Akt 1抑制剂）或CCT 128930（Akt 2抑制剂）预处理显著延迟Wnt 5a诱导的细胞迁移。转染ROR 2-Flag或ROR 2-siRNA分别上调或下调Akt的活化。最后，Wnt 5a/ROR 2信号传导不改变MG-63骨肉瘤细胞的细胞增殖。综上所述，我们证明ROR 2受体对Wnt 5a配体的应答激活PI 3 K/Akt/RhoA信号传导并促进骨肉瘤细胞的迁移。
We have reported that the phosphatidylinositol-3 kinase (PI3K)/Akt/RhoA signaling pathway mediates Wnt5a-induced cell migration of osteosarcoma cells. However, the specific receptors responding to Wnt5a ligand remain poorly defined in osteosarcoma metastasis. Wound healing assays were used to measure the migration rate of osteosarcoma cells transfected with shRNA or siRNA specific against ROR2 or indicated constructs. We evaluated the RhoA activation in osteosarcoma MG-63 and U2OS cells with RhoA activation assay. A panel of inhibitors of PI3K and Akt treated osteosarcoma cells and blocked kinase activity. Western blotting assays were employed to measure the expression and activation of Akt. Clonogenic assays were used to measure the cell proliferation of ROR2-knockdown or ROR2-overexpressed osteosarcoma cells. Wnt5a-induced osteosarcoma cell migration was largely abolished by shRNA or siRNA specific against ROR2. Overexpression of RhoA-CA (GFP-RhoA-V14) was able to rescue the Wnt5a-induced cell migration blocked by ROR2 knockdown. The Wnt5a-induced activation of RhoA was mostly blocked by ROR2 knockdown, and elevated by ROR2 overexpression, respectively. Furthermore, we found that Wnt5a-induced cell migration was significantly retarded by RhoA-siRNA transfection or pretreatment of HS-173 (PI3Kα inhibitor), MK-2206 (Akt inhibitor), A-674563 (Akt1 inhibitor), or CCT128930 (Akt2 inhibitor). The activation of Akt was upregulated or downregulated by transfected with ROR2-Flag or ROR2-siRNA, respectively. Lastly, Wnt5a/ROR2 signaling does not alter the cell proliferation of MG-63 osteosarcoma cells. Taken together, we demonstrate that ROR2 receptor responding to Wnt5a ligand activates PI3K/Akt/RhoA signaling and promotes the migration of osteosarcoma cells.
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