CXCL12/SDF-1α induces migration via SRC-mediated CXCR4-EGFR cross-talk in gastric cancer cells
CXCL12/SDF-1α induces migration via SRC-mediated CXCR4-EGFR cross-talk in gastric cancer cells
复制标题
CXCL12/SDF-1α 通过 SRC 介导的 CXCR4-EGFR 串扰诱导胃癌细胞迁移
DOI：
10.3892/ol.2017.6389
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发表时间：
2017-08-01
期刊：
影响因子：
2.9
通讯作者：
Liu, Yunpeng
中科院分区：
文献类型：
--
作者：
Cheng, Yu;Qu, Jinglei;Liu, Yunpeng
转移是晚期胃癌患者死亡的主要原因，多种信号通路促进了胃癌的发展。基质细胞衍生因子-1 （SDF-1 α /CXCL12）是CXC趋化因子受体-4 （CXCR4）的主要配体，在胃癌细胞迁移中起重要作用。既往研究表明，CXCL12还能刺激胃癌细胞分泌表皮生长因子受体（EGFR）配体，包括双调节蛋白和肝素结合的表皮生长因子样生长因子，导致迁移能力增强。然而，在胃癌中，CXCL12是否激活EGFR细胞内信号并因此刺激迁移尚不清楚。本研究证实3种胃癌细胞系SGC-7901、MGC-803和BGC-823均表达CXCR4。CXCL12刺激的趋化迁移能力增强被CXCR4拮抗剂AMD3100有效地消除。此外，Akt/细胞外信号调节激酶(ERK)/EGFR的快速磷酸化被证明参与了CXCL12/ cxcr4诱导的胃癌细胞迁移。敲低EGFR基因或使用抗EGFR单克隆抗体（C225）可阻断ERK/Akt的激活，并部分阻止CXCL12诱导的迁移能力，这表明EGFR信号位于CXCL12的下游。此外，研究还发现，CXCL12可促进非受体酪氨酸激酶c-类固醇受体共激活物（SRC）的激活和SRC/EGFR异源二聚体的形成，而SRC抑制剂PP2可阻断SRC/EGFR异源二聚体和EGFR的激活，以及CXCL12诱导的cxcr4介导的迁移。目前的研究结果表明，SRC介导潜在的CXCR4-EGFR串扰，从而利用EGFR-Akt/ERK轴促进细胞迁移。本研究为CXCL12/CXCR4通路在胃癌细胞迁移中的潜在调控机制提供了新的见解。
Metastasis is the primary cause of mortality in patients with advanced gastric carcinoma, and multiple signaling pathways promote the development of this condition. Stromal cell-derived factor-1 (SDF-1 alpha/CXCL12), the main ligand for CXC chemokine receptor-4 (CXCR4), serves an important role in gastric cancer cell migration. Previous studies have demonstrated that CXCL12 could also stimulate the secretion of epidermal growth factor receptor (EGFR) ligands, including amphiregulin and heparin-binding epidermal growth factor-like growth factor, from gastric cancer cells, resulting in an increase in the ability of migration. However, it remains to be elucidated whether CXCL12 activates EGFR intracellular signaling and therefore stimulates migration in gastric cancer. The present study demonstrated that three gastric cancer cell lines, SGC-7901, MGC-803 and BGC-823, all expressed CXCR4. The increased chemotactic migratory ability stimulated by CXCL12 was effectively abrogated by the CXCR4 antagonist, AMD3100. Furthermore, a rapid phosphorylation of Akt/extracellular signal-regulated kinase (ERK)/EGFR was demonstrated to be involved in CXCL12/CXCR4-induced gastric cancer cell migration. Knockdown of EGFR gene or the use of a monoclonal antibody against EGFR (C225) blocked the activation of ERK/Akt and partially prevented the ability of migration induced by CXCL12, which indicated that EGFR signaling is located downstream of CXCL12. In addition, it was also revealed that the activation of non-receptor tyrosine kinase c-steroid receptor co-activator (SRC) and the formation of the SRC/EGFR heterodimer are promoted by CXCL12, whereas the SRC inhibitor, PP2, blocks the SRC/EGFR heterodimer and the activation of EGFR, as well as CXCR4-meditated migration induced by CXCL12. The present results indicated that SRC mediates a potential CXCR4-EGFR cross-talk, and thereby utilizes the EGFR-Akt/ERK axis to promote cellular migration. The present study provided a novel insight into the underlying regulatory mechanisms of the CXCL12/CXCR4 pathway in gastric cancer cell migration.