Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop

Hypoxic tumor microenvironment(TME) is a universal feature in solid carcinoma and is associated with unfavorable prognosis. Tumor-derived exosomes are now significantly implicating in mediating cellular communication and interactions in TME. The aim of this study was to identify exosomal miR-301a-3p involved in gastric cancer(GC) progression and metastasis. Here, we found hypoxia promote GC exosomes release and miR-301a-3p expression in an HIF-1 alpha-dependent manner. In hypoxic TME, enriched miR-301a-3p could be transmitted between GC cells via exosomes and then contributed to inhibit HIF-1 alpha degradation through targeting PHD3, that were capable to hydroxylate HIF-1 alpha subunits to ubiquitinate degradation. This synergistical positive feedback loop between HIF-1 alpha and miR-301a-3p facilitated GC proliferation, invasion, migration, and epithelial-mesenchymal transition. In clinical samples, we further discovered circulating exosomal miR-301a-3p in serum was positively related with peritoneal metastasis. Collectively, these data indicate that GC cells could generate miR-301a-3p-rich exosomes in the hypoxic TME, which then help to HIF-1 alpha accumulation and promote GC malignant behaviors and metastasis. Exosomal miR-301a-3p/HIF-1 alpha signaling axis may serve as a promising predictor and potential therapeutic target of GC with metastasis.