Laminin-γ2–NR6A1 Fusion Protein Promotes Metastatic Potential in Non–Small-Cell Lung Carcinoma Cells without Epidermal Growth Factor Receptor Mutation

Laminin-γ2 fusion gene (Lm-γ2F), formed by translocation between LAMC2 and NR6A1, functions as an epidermal growth factor receptor (EGFR) ligand. However, its expression and impact on cancers beyond the initially studied contexts remain unclear. This study focused on Lm-γ2F protein secretion and its role in non-small-cell lung carcinoma (NSCLC), where EGFR signaling plays a pivotal role in malignancy progression. Lm-γ2F secretion was confirmed in serum-free conditioned medium from six NSCLC cell lines by Western blot analysis and further validated in NCI-H1650 cells. Hypothesizing that Lm-γ2F functions as an EGFR ligand, its effects in NSCLC cells lacking EGFR mutations were explored. In EKVX and RERF-LC-KJ cell lines, Lm-γ2F overexpression significantly enhanced cell growth, survival, motility, and invasiveness through EGFR signaling activation compared with controls. Conversely, no effects were observed in VMRC-LCD cells lacking EGFR expression. Additionally, increased membrane-type 1 matrix metalloproteinase expression was detected in Lm-γ2F-expressing EKVX cells. In vivo, these cells exhibited elevated metastatic activity in a lung metastasis model. These findings suggested that ectopic Lm-γ2F expression contributes to malignant progression in NSCLC cells without EGFR mutations. Furthermore, EGFR tyrosine kinase inhibitors may suppress metastasis in these contexts. This study provides novel insights into the oncogenic role of Lm-γ2F in NSCLC, highlighting its potential as a therapeutic target to mitigate tumor progression and metastasis.