Cancer-associated fibroblast miR-148a-5p/CALD1/collagen VI pathway promotes proliferation in Helicobacter pylori-positive gastric cancer.

PURPOSE: Helicobacter pylori (Hp) markedly elevates the risk of gastric cancer (GC) through the induction of chronic inflammation, which facilitates the accumulation of cancer-associated fibroblasts (CAFs) within the immune microenvironment of GC. CAFs contribute to the progression of GC and adversely affect subsequent therapeutic outcomes for patients. However, there is a paucity of research concerning the impact of Hp on CAFs or the identification of potential targets for therapeutic intervention. METHODS: We analyzed public microRNA and transcriptome sequencing data to identify key microRNAs and signaling pathways in Hp + GC. We also used single-cell sequencing to explore cellular localization and interaction mechanisms. Molecular biology experiments, in vitro cell co-culture, and in vivo cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models validated our findings and assessed the pathway's impact on GC proliferation and therapeutic potential. RESULTS: We identified the "TLR/miR-148a-5p/CALD1/collagen VI" signaling pathway in Hp-stimulated cancer-associated fibroblasts (CAFs) as a critical signaling pathway influencing the proliferation of Hp + GC. These CAFs contributed to GC cell proliferation by releasing substantial amounts of collagen VI, which interacted with tumoral SDC4 receptors. Administration of miR-148a-5p agomir in vivo effectively inhibited the proliferative effects and concurrently enhanced the efficacy of chemotherapy in Hp + GC mice models. CONCLUSION: Hp-stimulated CAFs played a significant role in promoting tumor proliferation in Hp + GC. Targeting its "TLR/miR-148a-5p/CALD1/collagen VI" pathway was a promising method to ease the collagen-rich microenvironment and inhibit the proliferation of GC cells. Furthermore, miR-148a-5p agomir might serve as a safer and more efficacious chemotherapeutic sensitizer for patients with Hp + GC.