Brain metastasis (BM) is associated with poor prognosis in patients with advanced non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutation reportedly enhances the development of BM. However, the exact mechanism of how EGFR-mutant NSCLC contributes to BM remains unknown. Herein, we found the protein WNT5A, was significantly downregulated in BM tissues and EGFR-mutant samples. In addition, the overexpression of WNT5A inhibited the growth, migration, and invasion of EGFR-mutant cells in vitro and retarded tumor growth and metastasis in vivo compared with the EGFR wide-type cells. We demonstrated a molecular mechanism whereby WNT5A be negatively regulated by transcription factor E2F1, and ERK1/2 inhibitor (U0126) suppressed E2F1’s regulation of WNT5A expression in EGFR-mutant cells. Furthermore, WNT5A inhibited β-catenin activity and the transcriptional levels of its downstream genes in cancer progression. Our research revealed the role of WNT5A in NSCLC BM with EGFR mutation, and proved that E2F1-mediated repression of WNT5A was dependent on the ERK1/2 pathway, supporting the notion that targeting the ERK1/2-E2F1-WNT5A pathway could be an effective strategy for treating BM in EGFR-mutant NSCLC.

晚期非小细胞肺癌（NSCLC）患者的脑转移（BM）与不良预后相关。据报道，表皮生长因子受体（EGFR）突变增强了BM的发展。然而，EGFR突变NSCLC如何促成BM的确切机制仍然未知。在本文中，我们发现蛋白质WNT5A在BM组织和EGFR突变样本中显着下调。另外，与EGFR宽型细胞相比，WNT5A的过表达在体外抑制了EGFR突变细胞的生长，迁移和侵袭，并在体内延迟了肿瘤的生长和转移。我们证明了一种分子机制，其中WNT5A被转录因子E2F1负调控，而ERK1 / 2抑制剂（U0126）抑制E2F1对EGFR突变细胞中WNT5A表达的调控。此外，WNT5A在癌症进展中抑制β-catenin活性及其下游基因的转录水平。我们的研究揭示了WNT5A在具有EGFR突变的NSCLC BM中的作用，并证明E2F1介导的WNT5A抑制作用依赖于ERK1 / 2途径，从而支持以ERK1 / 2-E2F1-WNT5A途径为靶点的观点EGFR突变型NSCLC中BM的治疗策略。