Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. The NF-κB-binding site III at -1692 to -1682 bp upstream from the transcript 1 start site in HAS3 proximal promoter was the most responsive to TNF-α-stimulated transcription. HAS3-derived HA release into extracellular milieu enhanced transendothelial monocyte migration and MCP-1 expression, which was attenuated by anti-HAS3 antibodies or a HAS inhibitor, 4-Methylumbelliferone (4-MU). HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 overexpression significantly increased oral cancer cell migration, invasion and xenograft tumorigenesis accompanied with the increased expression of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein 1 (MCP-1). Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. However, its role and mediation in oral cancer remains elusive. Hyaluronan (HA) is a major extracellular matrix component.

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