Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling
Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling
复制标题
DOI：
10.1038/onc.2009.175
复制
发表时间：
2009-09-10
期刊：
影响因子：
8
通讯作者：
Minami, Y.
中科院分区：
文献类型：
--
作者：
Enomoto, M.;Hayakawa, S.;Minami, Y.
受体酪氨酸激酶Ror 2通过作为Wnt 5a的受体或共受体来调节细胞迁移。尽管Wnt 5a与几种类型肿瘤的侵袭性有关，但Ror 2在肿瘤侵袭中的作用仍然难以捉摸。在这里，我们表明，骨肉瘤细胞系SaOS-2和U2 OS显示在体外通过激活Wnt 5a/Ror 2信号转导在细胞自主的方式的侵袭性。在骨肉瘤细胞中抑制Wnt 5a或Ror 2的表达抑制细胞侵袭性，伴随侵袭伪足形成减少。基因表达蛋白Lin将基质金属蛋白酶13（MMP-13）鉴定为在抑制Ror 2表达后在SaOS-2细胞中表达下调的基因之一。MMP-13的表达或活性降低抑制SaOS-2细胞的侵袭性。此外，MMP-13的表达和通过Wnt 5a/Ror 2信号传导的细胞侵袭性可以被Src家族蛋白酪氨酸激酶（SFKs）的抑制剂消除，表明SFKs通过Wnt 5a/Ror 2信号传导在MMP-13表达中的作用。我们进一步表明，SFK的激活被抑制的Ror 2的表达。总的来说，这些结果表明，Wnt 5a/Ror 2信号转导涉及SFK的激活，导致MMP-13的表达，并且组成型活性Wnt 5a/Ror 2信号转导以细胞自主的方式赋予骨肉瘤细胞侵袭性。Oncogene（2009）28，3197-3208; doi：10.1038/onc.2009.175; 2009年6月29日在线发表
The receptor tyrosine kinase Ror2 regulates cell migration by acting as a receptor or co-receptor for Wnt5a. Although Wnt5a has been implicated in the invasiveness of several types of tumors, the role of Ror2 in tumor invasion remains elusive. Here we show that osteosarcoma cell lines SaOS-2 and U2OS show invasive properties in vitro by activating Wnt5a/Ror2 signaling in a cell-autonomous manner. The suppressed expression of either Wnt5a or Ror2 in osteosarcoma cells inhibits cell invasiveness accompanying decreased invadopodia formation. Gene-expression pro. ling identified matrix metalloproteinase 13 (MMP-13) as one of the genes whose expression is downregulated in SaOS-2 cells following suppression of Ror2 expression. Reduced expression or activity of MMP-13 suppresses invasiveness of SaOS-2 cells. Moreover, expression of MMP-13 and cell invasiveness by Wnt5a/Ror2 signaling can be abrogated by an inhibitor of the Src-family protein tyrosine kinases (SFKs), suggesting the role of the SFKs in MMP-13 expression through Wnt5a/Ror2 signaling. We further show that activation of an SFK is inhibited by the suppressed expression of Ror2. Collectively, these results indicate that Wnt5a/Ror2 signaling involves the activation of a SFK, leading to MMP-13 expression, and that constitutively active Wnt5a/Ror2 signaling confers invasive properties on osteosarcoma cells in a cell-autonomous manner. Oncogene (2009) 28, 3197-3208; doi: 10.1038/onc.2009.175; published online 29 June 2009