KPNA2 promotes osteosarcoma progression by regulating the alternative splicing of DDX3X mediated by YBX1.

Osteosarcoma (OS) is a rapidly progressive primary malignant bone tumor that occurs in children and adolescents aged between 15 and 19 years and adults aged over 60 years. As alternative splicing (AS) changes caused by abnormal splicing factors contribute to tumor progression, gene expression and AS analyses were performed on 44 osteosarcoma patients to create a genome-wide co-expression network of RNA-binding proteins (RBPs), AS events, and AS genes. A gain- or loss-of-function osteosarcoma cell model was established, and an interactive network analysis and enrichment analysis were performed. Karyopherin Subunit Alpha 2 (KPNA2) negatively correlated with patient survival. KPNA2 transports splicing factor Y-box Binding Protein 1 (YBX1) into the nucleus and YBX1 accelerates the degradation of the ATP-dependent RNA helicase DDX3X (DDX3X) through the nonsense-mediated decay (NMD) pathway to promote intron retention of the DDX3X gene, thus reducing DDX3X protein levels. KPNA2/YBX1 axis regulates the stability of DDX3X mRNA and cell cycle progression. KPNA2/YBX1/DDX3X axis might be potential targets for inhibiting disease progression and improving OS patient survival. It integrates AS control of DDX3X into the progression of OS and represents a potential prognostic biomarker and therapeutic target for OS therapy.