tRF-3005a regulates exon skipping of SPAG4 by interacting with RALY to drive gastric cancer progression

Abstract Transfer RNA-derived fragments (tRFs) are emerging regulators in cancer, yet their role in the development and progression of gastric cancer (GC) remains unclear. Through RNA sequencing technology, this study identified a tRNA-derived fragment, tRF-3005a, that is significantly upregulated in GC tissues and cell lines and is associated with poor prognosis. Functionally, it promotes the proliferation, migration, and invasion of GC cells. Mechanistically, tRF-3005a bound to RALY, enhancing its interaction with SPAG4 mRNA, suppressing exon 8 skipping and leading to an increased generation of oncogenic SPAG4-L isoforms, thereby activating GRB14/PI3K/AKT signaling and ultimately promoting GC progression. This study reveals a novel mechanism wherein tRF-3005a promotes gastric cancer development by regulating RALY-mediated alternative splicing of SPAG4 to activate the GRB14/PI3K/AKT pathway, suggesting it may serve as a prognostic biomarker and therapeutic target.