Small Extracellular Vesicles-Derived Circ6718 Unlocks Stromal Remodeling and Serves as a Biomarker in Gastric Cancer

Small extracellular vesicles (sEVs)-derived circular RNA (circRNA) serves as a crucial biomarker for diagnosing gastric cancer and as a key regulator of tumor progression, orchestrating intercellular crosstalk within the tumor microenvironment (TME). In gastric cancer (GC), tissue-derived mesenchymal stem cells (GC-MSCs) critically drive tumor progression; however, the interplay between sEVs and circRNA in GC-MSCs remains incompletely understood. We identified sEVs-hsa_circ_0006718 (circ6718) as significantly upregulated in gastric cancer patients. Elevated levels of sEVs-circ6718 correlated with clinical stage, distant metastasis and poor prognosis, confirming its utility as both an early diagnostic and prognostic biomarker in GC. Mechanistically, circ6718 functions as a competing endogenous RNA (ceRNA) by sequestering hsa-miR-561-3p, thereby derepressing the expression of SAAL1 (Serum amyloid A-like 1). SAAL1 enhances the transcriptional activity of PRRX1 (Paired related homeobox 1), which directly activates the TGFβ1 promoter. Consequently, the TGFβ1/Smad2/3 signaling pathway drives the transdifferentiation of GC-MSCs into cancer-associated fibroblasts (CAFs)-promoting stromal remodeling and tumor aggressiveness. Our findings unveil a novel sEVs-circRNA-mediated axis in GC progression, revealing dual utility in diagnostics and targeted therapy.