tRF-Ser-TGA-011 impedes gastric cancer progression by targeting the MAP3K13/JNK signaling cascade.

[BACKGROUND] Early-stage gastric cancer (GC) is often asymptomatic, leading to frequent late-stage diagnoses. There is a critical need for non-invasive biomarkers to improve early detection and preoperative risk assessment. Although tRNA-derived fragments (tRFs) are increasingly implicated as key modulators in tumorigenesis, their functional significance and mechanistic roles in GC remain poorly understood.

[METHODS] We conducted high-throughput sequencing to characterize the tRFs' expression profiles between GC tissues and matched tumor-adjacent tissues. The level of tRF-Ser-TGA-011 (tRF-011) was validated via qRT-PCR in cell lines, tissues, and serum. Functional assays-such as CCK-8, colony formation, EdU incorporation, and flow cytometry-were employed to assess its role in proliferation and cell cycle progression. Mechanistic insights were gained through dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and western blotting. An in vivo xenograft model was established to evaluate tumor-suppressive effects.

[RESULTS] tRF-011 was identified as a pan-cancer diagnostic biomarker with high discriminative capacity. In GC, it distinguished patients from healthy controls with 79.2 % accuracy and stratified clinical stages with 77.4 % accuracy. High tRF-011 expression correlated significantly with improved progression-free survival. Functional experiments revealed that tRF-011 inhibition accelerated proliferation and cell cycle progression, while its overexpression suppressed tumor growth in vivo. Mechanistically, tRF-011 binds AGO2 to assemble a functional RISC complex, directly targeting MAP3K13 mRNA, downregulating JNK signaling, reducing Cyclin D1 expression, and arresting the cell cycle.

[CONCLUSIONS] Our findings establish tRF-011 as a promising non-invasive biomarker for GC diagnosis and staging, and highlight its therapeutic potential as a tumor suppressor through the AGO2-MAP3K13-JNK-Cyclin D1 axis.