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

purposeHelicobacter 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.

methodsWe 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.

resultsWe 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.

conclusionHp-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.