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Table 1_tRNA regulatory ecosystem states shape tissue and circulating small-RNA landscapes in gastric cancer.xlsx Jie Liu (15128) Yangyang Chen (1721638) Jiaqing Hu (9468089) Xujin Wei (13247547) Xiaoling Zheng (3022464) Cell Biology gastric cancer serum biomarker small-RNA sequencing tiRNA tRNA regulation tRNA-derived fragments tumour ecosystem Background<p>Gastric cancer is a heterogeneous disease shaped by the co-evolution of malignant epithelial programs, stromal remodeling, and immune contexture. Transfer RNA (tRNA) regulation sits at a strategic junction in this biology: it governs translational capacity and selectivity while generating tRNA-derived fragments (tRFs) and tRNA halves (tiRNAs)—a family of regulatory small RNAs detectable in both tissue and blood.</p>Objective<p>We asked whether the coordinated machinery responsible for tRNA transcription, maturation, modification, charging, and cleavage defines biologically meaningful gastric cancer ecosystem states, and whether a corresponding circulating small-RNA phenotype can be detected across independent cohorts of chronic atrophic gastritis (CAG), early gastric cancer (EGC), and gastric cancer (GC).</p>Methods<p>We integrated transcriptomic, genomic, proteomic, and tissue small-RNA data across complementary gastric cancer series and localized the program in single-cell expression maps. The clinical arm comprised independent serum samples from CAG, EGC, and GC participants.</p>Results<p>A 70-gene tRNA-regulatory program resolved three ecosystem states (TRES-1, TRES-2, and TRES-3). TRES-3 exhibited high tRNA-regulatory activity coupled with proliferative and DNA-repair protein expression, whereas TRES-1 was enriched for receptor-signaling and cell-cycle-restraint proteins. These states also differed in copy-number alterations and non-synonymous variant burden at the program level. Direct tissue small-RNA profiling revealed a marked expansion of tRF output and repertoire breadth in TRES-2 and TRES-3, with state-specific tRF classes, parent-tRNA modules, and exact sequences. A shared set of 446 exact tRF sequences connected the tissue and serum catalogues. In an independent gastric cancer series, the three-state architecture aligned with ACRG molecular subtypes, RNA cargo selection, extracellular vesicle release, and stress-response programs. Single-cell mapping placed tRNA-regulatory activity across epithelial, stromal, and immune compartments. In our serum cohort, the 14-30-nt fraction declined from 47.4% in CAG to 37.8% in EGC and 33.6% in GC, while the 31-40-nt fraction rose from 52.6% to 62.2% and 66.4% (absolute Spearman rho = 0.791; BH-adjusted P = 0.0112; exact-permutation P = 0.0214).</p>Conclusion<p>tRNA regulation defines gastric cancer ecosystem states with distinct genomic, proteomic, and tissue small-RNA correlates. In our serum cohort, the reciprocal shift in circulating tRF/tiRNA length composition—a decline in the 14-30-nt fraction and a rise in the 31-40-nt fraction—parallels the transition from CAG to EGC to GC. These findings establish a testable molecular framework for paired tissue-serum validation and position circulating tRF/tiRNA architecture as a candidate readout of gastric cancer ecosystem biology.</p> 2026-10-02T05:33:16Z Dataset Dataset 10.3389/fcell.2026.1960697.s001 https://figshare.com/articles/dataset/Table_1_tRNA_regulatory_ecosystem_states_shape_tissue_and_circulating_small-RNA_landscapes_in_gastric_cancer_xlsx/34054290 CC BY 4.0