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

Abstract To investigate the function of RBM39 in lung adenocarcinoma (LUAD), with a particular focus on its regulatory effect on the alternative splicing of NRG1-206 and its role in tumor progression. Differential expression analysis of RNA binding proteins (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 was employed to explore RBM39-mediated gene expression and alternative splicing regulation, and iRIP-seq combined with bioinformatics tools was used to identify binding motifs and downstream targets. Our results indicated that RBM39 expression was significantly downregulated in LUAD tissues and was associated with poor prognosis. Overexpression of RBM39 in A549 cells significantly 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 direct binding of RBM39 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. Overall, RBM39 exerts an antitumor effect in A549 cells by regulating gene expression and alternative splicing, largely by inhibiting the generation of the oncogenic NRG1-206 isoform to suppress malignant progression, highlighting its potential as a therapeutic target for LUAD.