Department of Neurosurgery, Tianjin First Central Hospital, Tianjin, 300192, PR China.
Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, PR China.
Exp Cell Res. 2020 Apr 1;389(1):111893. doi: 10.1016/j.yexcr.2020.111893. Epub 2020 Feb 5.
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.
与非侵袭性肿瘤细胞相比，神经胶质瘤细胞过度表达趋化因子受体 4（CXCR4），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（CXCL12，也称为基质衍生因子-1，SDF-1）及其细胞表面受体 CXCR4 激活信号轴，诱导膜型 2 基质金属蛋白酶（MT2-MMP）的表达，在各种癌细胞的侵袭和迁移中起着关键作用；然而，其具体机制尚不清楚。最近的研究表明，侵袭伪足可以募集和分泌相关酶，如基质金属蛋白酶（MMPs），来降解周围的细胞外基质（ECM），促进肿瘤细胞的侵袭和迁移。磷酸化的桩蛋白（pY421-cortactin）是侵袭伪足形成和成熟所必需的，但涉及磷酸化的上游调节因子和激酶尚未阐明。在本研究中，我们发现 CXCL12/CXCR4 能够诱导神经胶质瘤细胞侵袭伪足的形成，可能是通过调节桩蛋白的磷酸化。在神经胶质瘤细胞中证实了桩蛋白和 Arg（也称为 Abl 相关非受体酪氨酸激酶，ABL2）的相互作用。沉默 Arg 通过阻断桩蛋白磷酸化抑制神经胶质瘤细胞侵袭伪足的形成和侵袭。此外，CXCL12 不能诱导 Arg 敲低的神经胶质瘤细胞中的神经胶质瘤细胞侵袭。基于这些结果，可以得出结论，Arg 介导 CXCL12/CXCR4 诱导的神经胶质瘤细胞侵袭，CXCL12/CXCR4 通过 Arg-cortactin 途径调节侵袭伪足的成熟，这表明 Arg 可能是抑制神经胶质瘤细胞侵袭的候选治疗靶点。
