Arg kinase mediates CXCL12/CXCR4-induced invadopodia formation and invasion of glioma cells
Arg kinase mediates CXCL12/CXCR4-induced invadopodia formation and invasion of glioma cells
复制标题
Arg激酶介导CXCL12/CXCR4诱导的胶质瘤细胞侵袭伪足形成和侵袭
DOI：
10.1016/j.yexcr.2020.111893
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发表时间：
2020-04-01
影响因子：
3.7
通讯作者：
Yang, Xuejun
中科院分区：
文献类型：
--
作者：
Chen, Lei;Zhu, Meng;Yang, Xuejun
与非侵袭性肿瘤细胞相比，胶质瘤细胞过度表达趋化因子受体4（CXCR 4），其在侵袭性肿瘤细胞中的表达显著高于非侵袭性肿瘤细胞。C-X-C基序趋化因子配体12（CXCL 12，也称为基质衍生因子-1，SDF-1）及其细胞表面受体CXCR 4激活诱导膜型2型基质金属蛋白酶（MT 2-MMP）表达的信号传导轴，其在各种癌细胞的侵袭和迁移中起关键作用;然而，涉及其中的具体机制尚不清楚。近年来的研究表明，侵袭伪足可以募集并分泌相关的酶，如基质金属蛋白酶（matrix metalloproteinases，MMPs），降解周围的细胞外基质（extracellular matrix，ECM），促进肿瘤细胞的侵袭和迁移。磷酸化coronylated n（pY 421-coronylated n）是侵入伪足形成和成熟所必需的，但参与磷酸化的上游调节因子和激酶尚未阐明。在这项研究中，我们发现CXCL 12/CXCR 4能够诱导胶质瘤细胞侵袭伪足的形成，可能是通过调节coronin磷酸化。证明了胶质瘤细胞中corneum和Arg（也称为corneum相关的非受体酪氨酸激酶，ABL 2）的相互作用。沉默Arg基因可通过阻断coronin的磷酸化而抑制胶质瘤细胞侵袭伪足的形成和侵袭。此外，CXCL 12不能诱导Arg敲低的胶质瘤细胞的胶质瘤细胞侵袭。结果表明，Arg介导了CXCL 12/CXCR 4诱导的胶质瘤细胞侵袭，CXCL 12/CXCR 4通过Arg-coronin途径调控侵袭足的成熟，提示Arg可能成为抑制胶质瘤细胞侵袭的候选治疗靶点。
Compared with noninvasive tumor cells, glioma cells overexpress chemokine receptor type 4 (CXCR4), which exhibits significantly greater expression in invasive tumor cells than in noninvasive tumor cells. C-X-C motif chemokine ligand 12 (CXCL12, also known as stromal derived factor-1, SDF-1) and its cell surface receptor CXCR4 activate a signaling axis that induces the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), which plays a pivotal role in the invasion and migration of various cancer cells; however, the specific mechanism involved in this is unclear. Recently, studies have shown that invadopodia can recruit and secrete related enzymes, such as matrix metalloproteinases (MMPs), to degrade the surrounding extracellular matrix (ECM), promoting the invasion and migration of tumor cells. Phosphorylated cortactin (pY421-cortactin) is required for the formation and maturation of invadopodia, but the upstream regulatory factors and kinases involved in phosphorylation have not been elucidated. In this study, we found that CXCL12/CXCR4 was capable of inducing glioma cell invadopodia formation, probably by regulating cortactin phosphorylation. The interaction of cortactin and Arg (also known as Abl-related nonreceptor tyrosine kinase, ABL2) in glioma cells was demonstrated. The silencing of Arg inhibited glioma cell invadopodia formation and invasion by blocking cortactin phosphorylation. Moreover, CXCL12 could not induce glioma cell invasion in Arg-knockdown glioma cells. Based on these results, it can be concluded that Arg mediates CXCL12/CXCR4-induced glioma cell invasion, and CXCL12/CXCR4 regulates invadopodia maturation through the Arg-cortactin pathway, which indicates that Arg could be a candidate therapeutic target to inhibit glioma cell invasion.