{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:55:23Z","timestamp":1790920523852,"version":"4.1.0"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2026J01120285"],"award-info":[{"award-number":["2026J01120285"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2026J001535"],"award-info":[{"award-number":["2026J001535"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats: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)\u2014a family of regulatory small RNAs detectable in both tissue and blood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats: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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats: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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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\u2014a decline in the 14-30-nt fraction and a rise in the 31-40-nt fraction\u2014parallels 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1960697","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T05:35:22Z","timestamp":1790919322000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["tRNA regulatory ecosystem states shape tissue and circulating small-RNA landscapes in gastric cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Jie","family":"Liu","sequence":"first","affiliation":[{"name":"Digestive Endoscopy Center, Fuzhou University Affiliated Provincial Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Digestive Endoscopy Center, Fuzhou University Affiliated Provincial Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqing","family":"Hu","sequence":"additional","affiliation":[{"name":"Digestive Endoscopy Center, Fuzhou University Affiliated Provincial Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujin","family":"Wei","sequence":"additional","affiliation":[{"name":"Endoscopic Center, The First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, Fujian, China"]},{"name":"Endoscopic Center, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Zheng","sequence":"additional","affiliation":[{"name":"Digestive Endoscopy Center, Fuzhou University Affiliated Provincial Hospital","place":["Fuzhou, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nature13480","article-title":"Comprehensive molecular characterization of gastric adenocarcinoma","volume":"513","year":"2014","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"216701","DOI":"10.1016\/j.canlet.2024.216701","article-title":"Biological functions and clinical significance of tRNA-derived small fragments in tumors: current state and future perspectives","volume":"587","author":"Chen","year":"2024","journal-title":"Cancer Lett."},{"key":"B3","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/nm.3850","article-title":"Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes","volume":"21","author":"Cristescu","year":"2015","journal-title":"Nat. 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