Cancer Med. 2026 Apr;15(4):e71833. doi: 10.1002/cam4.71833.

ABSTRACT

OBJECTIVES: This study aims to elucidate the role of FGFR1 in activating the Wnt/β-catenin signaling pathway and the underlying mechanisms by which it promotes malignant progression in lung squamous cell carcinoma (LUSC). By integrating multi-omics analysis with functional experiments, the clinical heterogeneity of FGFR1 amplification, signaling crosstalk, and their regulatory networks governing tumor phenotypes were revealed.

METHODS: Using TCGA data (n = 490), we analyzed the relationship between FGFR1 copy number variation (CNV) and mRNA expression in LUSC, and validated the correlation with protein expression in a clinical cohort (n = 38). GSEA and single-gene GSEA were performed to identify signaling pathways associated with high FGFR1 expression. The interaction between FGFR1 and the Wnt/β-catenin pathway was investigated by immunohistochemistry, immunofluorescence, stable cell lines, Western blot, qPCR, and functional assays.

RESULTS: FGFR1 amplification correlated with increased mRNA and protein expression. The top 25% FGFR1 high-expression group enriched Wnt/β-catenin, PI3K-Akt, and cAMP pathways. Mechanistically, FGFR1 promoted β-catenin nuclear accumulation and enhanced β-catenin signaling through PKA-associated phosphorylation and Akt/GSK3β-related regulation of β-catenin stability, and these effects were attenuated by AKT inhibition. CTNNB1 knockdown significantly inhibited proliferation, migration, invasion, and tumor growth of LUSC cells.

CONCLUSIONS: Our findings indicate that FGFR1 activates Wnt/β-catenin signaling through coordinated regulation of β-catenin phosphorylation, stability, and subcellular localization, thereby promoting malignant progression in LUSC. These results provide a rationale for targeting the FGFR1-Wnt/β-catenin axis as a potential therapeutic strategy.

PMID:41998829 | DOI:10.1002/cam4.71833