Hypoxia-Mediated Downregulation of Exosomal miR-128-3p Promotes Lymphangiogenesis via VEGF-C in Oral Squamous Cell Carcinoma.

Background: Cancer cell-derived exosomal microRNAs (miRNAs) are crucial mediators of intercellular communication within the tumor microenvironment, including with lymphatic endothelial cells (LECs). Hypoxia, a key driver of tumor aggressiveness, modulates exosome release and cargo. However, the specific functions of exosomal miRNAs derived from hypoxic oral squamous cell carcinoma (OSCC) cells are not well defined. Methods: We employed a two-phase strategy. In the discovery phase, miRNA sequencing was performed on exosomes from hypoxic exosomes and normoxic exosomes (Norm-exos) Tca-8113 cells, and their pro-lymphangiogenic effects on Human LECs (HLECs) were assessed. In the validation phase, using SCC-9 cells, we investigated the functional role of a candidate miRNA, miR-128-3p, through gain-of-function experiments and identified its target. Results: Hypoxic OSCC-derived exosomes (Hypo-exos) were internalized by HLECs and significantly enhanced their proliferation, migration, and tube formation. miR-128-3p was markedly downregulated in Hypo-exos. Overexpression of miR-128-3p reversed the pro-lymphangiogenic effects of Hypo-exos and reduced vascular endothelial growth factor (VEGF)-C expression. A dual-luciferase reporter assay confirmed VEGF-C as a direct target of miR-128-3p. Conclusion: Hypo-exos promote lymphangiogenesis, partly through the downregulation of exosomal miR-128-3p, which directly targets and inhibits VEGF-C. This novel miR-128-3p/VEGF-C axis presents a potential therapeutic target for mitigating lymphangiogenesis and metastasis in OSCC.