Authors
Qiang Li, Jianing Yang, Luhong Cao, Qiushuang Wang, Junfeng Yan, Guiyang Ye, Linxue Huang, Yi Wang, Qiang Tong
Published in
Cancer letters. Pages 218832. Sep 08, 2026. Epub Sep 08, 2026.
Abstract
Recurrence and peritoneal metastasis remain major challenges in gastric cancer (GC), highlighting the need to identify actionable stromal-tumor signaling circuits within the tumor microenvironment (TME). Integrated transcriptomic analyses and clinical validation identified TAGLN as a fibroblast-enriched factor associated with GC progression and poor prognosis. Functional studies showed that TAGLN expression in cancer-associated fibroblasts (CAFs) enhanced HGF production, at least in part through NF-κB activation, thereby promoting GC-cell malignant phenotypes via paracrine HGF/c-MET signaling. Mechanistically, HGF/c-MET activation promoted DDX5 phosphorylation, with Tyr595 identified as a critical phosphorylation site, and increased DDX5 nuclear accumulation. Nuclear DDX5 was enriched at the CAV1 promoter and enhanced CAV1 transcription, whereas CAV1 promoted malignant phenotypes by activating the PI3K/AKT/mTOR signaling. Salvianolic acid A (SA-A) showed TAGLN target engagement in DARTS and CETSA assays and attenuated TAGLN-associated CAF activity. In vivo, SA-A suppressed CAF-driven tumor growth and peritoneal dissemination. Collectively, these findings define a CAF-TAGLN/HGF/c-MET/DDX5/CAV1 signaling cascade linking stromal activation to tumor-cell transcriptional reprogramming and CAF-tumor crosstalk within the TME, and identify TAGLN as a potential therapeutic vulnerability for microenvironment-directed intervention in GC.
PMID:
42710828
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.
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