RBM39 regulates malignant progression in lung adenocarcinoma cells through alternative splicing of NRG1-206

Purpose: To investigate the function of RBM39 in lung adenocarcinoma (LUAD), particularly its regulatory effect on NRG1-206 alternative splicing and its role in tumor progression.Methods: Differential expression analysis of RBPs in LUAD samples was performed using TCGA datasets. RBM39 expression levels were validated by RT-qPCR and western blot. Functional assays, including cell proliferation, apoptosis, invasion, and migration were conducted using A549 cells with RBM39 or NRG1-206 overexpression. RNA-seq, alternative splicing analysis, and iRIP-seq were used to explore RBM39-mediated gene expression and splicing regulation. Binding motifs and downstream targets were identified via bioinformatics tools.Results: RBM39 was significantly downregulated in LUAD tissues and associated with poor prognosis. Overexpression of RBM39 in A549 cells inhibited proliferation and invasion while promoting apoptosis (all p<0.05). Transcriptomic profiling revealed that RBM39 regulated gene expression and alternative splicing, with enrichment in immune and transcriptional pathways. iRIP-seq confirmed that RBM39 is directly bound to pre-mRNAs including NRG1. Notably, RBM39 modulated the alternative splicing of NRG1, particularly suppressing the oncogenic NRG1-206 isoform. Functional rescue experiments showed that overexpression of NRG1-206 reversed the tumor-suppressive effects of RBM39.Conclusion: RBM39 acts as a tumor suppressor in A549 cells by regulating gene expression and alternative splicing. It inhibits malignant progression through direct suppression of the oncogenic NRG1-206 isoform, highlighting its potential as a therapeutic target in LUAD.