CircSRPK1 mediated by the exon junction complex promotes gastric cancer progression by interacting with hnRNP A2B1 to regulate RON mRNA alternative splicing

作者：Shanshan Yu, Ming Chen, Kecheng Jiang, Cheng Chen, Jinxiao Liang, Jingjing Zheng, Bin Lou, Jun Lü, Xiaohua Zhu, Donghui Zhou · 发表于：Cancer Letters · 年份：2025 · DOI：10.1016/j.canlet.2025.217879 · 被引用次数：4 · 研究领域：Circular RNAs in diseases、RNA Research and Splicing、Viral Infections and Immunology Research

Gastric cancer (GC) is one of the most common malignant tumors with high heterogeneity, and its etiology and pathogenesis are unclear. Recently, many aberrantly alternatively spliced isoforms of the receptor tyrosine kinase recepteur d'origine nantais (RON) have been shown to play vital roles in GC development. Serine/arginine protein kinase 1 (SRPK1) is widely recognized as a key splicing factor kinase that regulates various steps of alternative splicing. Recent studies on SRPK1 have focused mainly on splicing activity, but the role of SRPK1-derived circular RNAs in RON alternative splicing and GC progression is unknown. Among all SRPK1-derived circRNAs in the CircInteractome, hsa_circ_0076168 (henceforth called circSRPK1) was upregulated in GC tissues compared with adjacent normal tissues, which was often associated with adverse outcomes in GC patients. Functionally, circSRPK1 promoted the malignant phenotype of GC. Mechanistically, circSRPK1 directly interacted with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNP A2B1) to promote its nuclear translocation and binding to the exonic splicing enhancer (ESE) element on RON mRNA; this regulated the alternative splicing of downstream RON mRNA, induced RONΔ160 production, and ultimately promoted GC progression. More importantly, circSRPK1 production in GC cells was regulated by a component of the exon junction complex MAGOH, which enhanced the binding of EIF4A3 to the circSRPK1 transcript. Additionally, MAGOH knockdown rescue...