Targeting FOXE1-Mediated LAMC2 Expression to Improve Preoperative Chemoradiotherapy Outcomes in Lung Cancer Patients at Risk of Brain Metastasis.

Objective

This study elucidated the role of the forkhead box E1 (FOXE1)-laminin γ2 (LAMC2) signaling axis in promoting brain metastasis (BM) of lung cancer and evaluated its potential as a therapeutic target to enhance the efficacy of preoperative chemoradiotherapy (CRT).

Methods

Bioinformatics analysis of the GSE126548 dataset revealed a significant association between elevated FOXE1 expression and BM in lung cancer patients. Functional in vitro assays-including real-time polymerase chain reaction, Western blotting, migration, invasion, and endothelial permeability assays-were conducted in lung cancer cells and human umbilical vein endothelial cells exposed to tumor-conditioned media. In addition, in vivo xenograft and BM mouse models were established to assess the impact of FOXE1 on tumor growth, metastatic potential, and treatment responsiveness.

Results

FOXE1 knockdown significantly inhibited lung cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistically, LAMC2 was identified as a downstream effector of FOXE1, with rescue experiments confirming that the FOXE1-LAMC2 axis plays a central role in driving tumor progression and brain metastatic potential. Notably, FOXE1 silencing enhanced sensitivity to CRT in preclinical models.

Conclusions

FOXE1 promotes lung cancer progression and BM by upregulating LAMC2. Targeting the FOXE1-LAMC2 pathway may improve the efficacy of preoperative CRT and offers a promising strategy for therapeutic intervention in lung cancer patients at high risk of BM.