Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).
Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China (mainland).
Med Sci Monit. 2020 Sep 3;26:e925019. doi: 10.12659/MSM.925019.
BACKGROUND Previous studies have established cross-talk between CXC chemokine receptor 4 (CXCR4) and epidermal growth factor receptor (EGFR) in gastric cancer, however, the effect of dual CXCR4/EGFR tumor status on patient survival and mechanisms regulating expression has yet to be investigated. MATERIAL AND METHODS A total of 56 gastric cancer patients were recruited to reveal the relationship between CXCR4 and EGFR expression, and the clinic-pathological features of samples were investigated by immunohistochemical staining. Two gastric cancer cell lines were treated with CXCL12 or EGF, and expression levels of CXCR4 and EGFR were detected by reverse-transcription-polymerase chain reaction and western blotting. Cells were treated with an NF-kappaB pathway inhibitor to investigate its role in the regulation of CXCL12 or EGF-mediated CXCR4 and EGFR expression and migration ability. RESULTS The results show that CXCL12 upregulated CXCR4 and EGFR. Similarly, EGF could induce the expression of CXCR4 and contribute to gastric cancer cell metastasis. In addition, both CXCL12 and EGF could induce the activation of IKKalphaß and P65. Conversely, suppression of the NF-kappaB pathway remarkably decreased the expression of CXCR4/EGFR and migration ability induced by EGF or CXCL12. Furthermore, a significantly positive correlation between CXCR4 and EGFR expression was observed in gastric cancer patient tissues (r=0.372, P=0.005). Samples expressing both receptors had significantly poorer patient prognosis than other patient groups (P=0.002). CONCLUSIONS Our results showed that the CXCL12/CXCR4 and EGF/EGFR axis can regulate the expression of each other through the NF-kappaB pathway to promote metastasis. These data suggested that simultaneous inhibition of EGFR and CXCR4 may be a potential therapeutic strategy in gastric cancer.
先前的研究已经证实了趋化因子受体 4（CXCR4）与表皮生长因子受体（EGFR）在胃癌中的相互作用，然而，双重 CXCR4/EGFR 肿瘤状态对患者生存的影响及其调控表达的机制仍有待研究。
共招募了 56 名胃癌患者，通过免疫组织化学染色揭示 CXCR4 和 EGFR 表达之间的关系，并对样本的临床病理特征进行了研究。用 CXCL12 或 EGF 处理两种胃癌细胞系，通过逆转录聚合酶链反应和 Western blot 检测 CXCR4 和 EGFR 的表达水平。用 NF-κB 通路抑制剂处理细胞，以研究其在调节 CXCL12 或 EGF 介导的 CXCR4 和 EGFR 表达和迁移能力中的作用。
结果表明，CXCL12 上调了 CXCR4 和 EGFR。同样，EGF 也能诱导 CXCR4 的表达并促进胃癌细胞的转移。此外，CXCL12 和 EGF 均可诱导 IKKαβ 和 P65 的激活。相反，抑制 NF-κB 通路可显著降低 EGF 或 CXCL12 诱导的 CXCR4/EGFR 表达和迁移能力。此外，在胃癌患者组织中观察到 CXCR4 和 EGFR 表达之间存在显著的正相关（r=0.372，P=0.005）。表达两种受体的样本的患者预后明显比其他患者组差（P=0.002）。
我们的结果表明，CXCL12/CXCR4 和 EGF/EGFR 轴可以通过 NF-κB 通路相互调节对方的表达，从而促进转移。这些数据表明，同时抑制 EGFR 和 CXCR4 可能是胃癌的一种潜在治疗策略。
