E2F1-mediated repression of WNT5A expression promotes brain metastasis dependent on the ERK1/2 pathway in EGFR-mutant non-small cell lung cancer

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 beta-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.

Automated summary

In this study, WNT5A protein was found to be significantly downregulated in BM tissues and EGFR-mutant samples of NSCLC patients, with overexpression inhibiting the growth and migration of EGFR-mutant cells. Further research revealed that WNT5A is negatively regulated by E2F1 and that its repression is dependent on the ERK1/2 pathway in EGFR-mutant cells. These findings suggest that targeting the ERK1/2-E2F1-WNT5A pathway could be an effective strategy for treating BM in EGFR-mutant NSCLC.