Identification and Validation of Critical Alternative Splicing Events and Splicing Factors in GC Progression in Gastric Cancer

Abstract

Background: Gene expression and alternative splicing (AS) interact in complex ways to regulate biological process associated with cancer development. Here, we evaluated both gene expression and AS events to determine hub AS events and explore their clinical significance. Methods: RNA-seq data, clinical data, and AS events were obtained for a 348 GC patient samples from the TCGA and TCGASpliceSeq databases. Cox univariable and multivariable analyses, KEGG and GO pathway analyses, Protein-protein interaction (PPI) networks analysis were performed to identify hub AS events and splicing factor/spliceosome genes, which were further validated in 53 GCs. Findings: By bioinformatics methods, gene AS event- and gene expression-mediated GC progression shared the same mechanisms, such as PI3K/AKT pathway, but the involved genes were different. Although expression of 17 hub AS events were confirmed in 53 GC tissues, only 10 AS events in seven genes were identified as critical candidates related to GC progression, notably the AS events (Exon Skip) in CLSTN1 and SEC16A. These AS events varied in GC correlated to activation of the PI3K/AKT pathway. Gene AS events and expression showed distinct correlations with clinical parameters and prognosis. Besides, we further revealed that QKI and NOVA1 were the crucial splicing factors regulating AS events in GC. Interpretation: Our integrated analysis revealed hub AS events in GC development, which may be the potential therapeutic targets for GC. Funding Statement: Financial support from National Natural Science Foundation of China; Number: 81772558; Shanghai Hospital Development Center; Number: 16CR2064B; Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine; Number: 2018zy09 and Shanghai Municipal Commission of Health and Family Planning; Number: 201540026. Declaration of Interests: The authors have declared that there are no conflicts of interest. Ethics Approval Statement: This study was approved by the Ethical Review Committee of Ruijin Hospital of Shanghai Jiaotong University. All patients provided signed informed consent.