{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["15"],"submitter":["Su P"],"pubmed_abstract":["<h4>Background</h4>Alternative splicing (AS) of mRNA has emerged as a promising biomarker for various tumors, playing a crucial role throughout nearly all stages of tumor progression and influencing the tumor immune microenvironment (TIME). Our study was designed to develop an AS-based signature for accurate prognosis prediction in lung adenocarcinoma (LUAD) patients, to delineate the associated immune cell landscape, and to pinpoint promising drug targets.<h4>Methods</h4>Prognostic alternative splicing events (PASEs) were identified through univariate Cox regression analysis of RNA-Seq data from The Cancer Genome Atlas (TCGA). These PASEs were incorporated into a least absolute shrinkage and selection operator-Cox proportional hazards model to develop a prognostic signature. Experimental validation was performed using reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and functional assays <i>in vitro</i> and <i>in vivo</i>.<h4>Results</h4>A total of 13 PASEs were selected to form the prognostic signature, which demonstrated excellent predictive power for 1-, 2-, and 3-year overall survival (OS), with area under the receiver operating characteristic curve values of 0.776, 0.751, and 0.767, respectively. High-risk patients, identified by the signature, showed significantly decreased stromal, immune, and combined scores; increased tumor purity (<i>P</i>< 0.001); a reduced prevalence of various immune cell types; diminished immune cell activity; and decreased expression of immune checkpoint genes. Notably, elevated expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), a gene associated with PASEs, correlated with poorer OS and significantly higher infiltration of CD8<sup>+</sup> T cells, activated memory CD4<sup>+</sup> T cells, and M1 macrophages compared to patients with lower expression. Further validation studies confirmed increased CDKN2A levels in LUAD tissues, with CDKN2A protein expression inversely correlated with LUAD prognosis (hazard ratio = 2.737; 95% confidence interval, 1.524-4.915; <i>P</i> = 0.0002). CDKN2A was found to promote LUAD progression <i>in vitro</i>. Molecular docking identified YM-201636 and VE-822 (Berzosertib) as potential drugs targeting CDKN2A, both showing promise for LUAD treatment <i>in vivo</i>.<h4>Conclusion</h4>PASEs constitute a comprehensive biomarker for predicting prognosis and monitoring the TIME in LUAD patients. Specifically, CDKN2A stands out as a potential prognostic biomarker and drug target for LUAD."],"journal":["Frontiers in oncology"],"pagination":["1579017"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12669014"],"repository":["biostudies-literature"],"pubmed_title":["Prognostic alternative mRNA splicing in lung adenocarcinoma."],"pmcid":["PMC12669014"],"pubmed_authors":["Xu P","Su P","Xu D"],"additional_accession":[]},"is_claimable":false,"name":"Prognostic alternative mRNA splicing in lung adenocarcinoma.","description":"<h4>Background</h4>Alternative splicing (AS) of mRNA has emerged as a promising biomarker for various tumors, playing a crucial role throughout nearly all stages of tumor progression and influencing the tumor immune microenvironment (TIME). Our study was designed to develop an AS-based signature for accurate prognosis prediction in lung adenocarcinoma (LUAD) patients, to delineate the associated immune cell landscape, and to pinpoint promising drug targets.<h4>Methods</h4>Prognostic alternative splicing events (PASEs) were identified through univariate Cox regression analysis of RNA-Seq data from The Cancer Genome Atlas (TCGA). These PASEs were incorporated into a least absolute shrinkage and selection operator-Cox proportional hazards model to develop a prognostic signature. Experimental validation was performed using reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and functional assays <i>in vitro</i> and <i>in vivo</i>.<h4>Results</h4>A total of 13 PASEs were selected to form the prognostic signature, which demonstrated excellent predictive power for 1-, 2-, and 3-year overall survival (OS), with area under the receiver operating characteristic curve values of 0.776, 0.751, and 0.767, respectively. High-risk patients, identified by the signature, showed significantly decreased stromal, immune, and combined scores; increased tumor purity (<i>P</i>< 0.001); a reduced prevalence of various immune cell types; diminished immune cell activity; and decreased expression of immune checkpoint genes. Notably, elevated expression of cyclin-dependent kinase inhibitor 2A (CDKN2A), a gene associated with PASEs, correlated with poorer OS and significantly higher infiltration of CD8<sup>+</sup> T cells, activated memory CD4<sup>+</sup> T cells, and M1 macrophages compared to patients with lower expression. Further validation studies confirmed increased CDKN2A levels in LUAD tissues, with CDKN2A protein expression inversely correlated with LUAD prognosis (hazard ratio = 2.737; 95% confidence interval, 1.524-4.915; <i>P</i> = 0.0002). CDKN2A was found to promote LUAD progression <i>in vitro</i>. Molecular docking identified YM-201636 and VE-822 (Berzosertib) as potential drugs targeting CDKN2A, both showing promise for LUAD treatment <i>in vivo</i>.<h4>Conclusion</h4>PASEs constitute a comprehensive biomarker for predicting prognosis and monitoring the TIME in LUAD patients. Specifically, CDKN2A stands out as a potential prognostic biomarker and drug target for LUAD.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025","modification":"2026-06-08T03:17:57.253Z","creation":"2026-06-08T03:09:05.34Z"},"accession":"S-EPMC12669014","cross_references":{"pubmed":["41341386"],"doi":["10.3389/fonc.2025.1579017"]}}