Abstract
Hyaluronan (HA) is a major extracellular matrix component. However, its role and mediation in oral cancer remains elusive. Hyaluronan synthase 3 (HAS3), involved in pro-inflammatory short chain HA synthesis, was the predominant synthase in oral cancer cells and tissues. 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). Conversely, HAS3 depletion abrogated HAS3-mediated stimulation. HAS3 induced oncogenic actions partly through activating EGFR-SRC signaling. 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). 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. ChIP-qPCR analysis confirmed the highest NF-κB-p65 enrichment on site III. Increased HAS3 mRNA expression was negatively correlated with the overall survival of oral cancer patients. A concomitant increase of TNF-α, a stimulus for HAS3 expression, with HAS3 expression was not only associated with lymph node metastasis but also negated clinical outcome. Together, HAS3 and TNF-α formed an inter-regulation loop to enhance tumorigenesis in oral cancer.
Highlights
Hyaluronan (HA), a polysaccharide of repeating units of D-glucuronic acid and N-acetyl-glucosamine in body fluids and tissues, is an essential component of extracellular matrix [1]
Hyaluronan synthase 3 (HAS3) mRNA was most expressed in 5 oral cancer lines (Figure 1A)
We further compared the expression in oral cancer cells with normal counterparts, Normal oral keratinocytes (NOK) or Displastic oral keratinocytes (DOK)
Summary
Hyaluronan (HA), a polysaccharide of repeating units of D-glucuronic acid and N-acetyl-glucosamine in body fluids and tissues, is an essential component of extracellular matrix [1]. In addition to regulating inflammatory gene expression, immune cell recruitment, and cytokine release [4], HA promotes tumor angiogenesis [5]. HAS2 is the most studied synthase involved in embryonic and cardiac cushion morphogenesis and can stimulate cell proliferation and angiogenesis, HAS3 is the most active in the synthesis of short chain HA (100~1000 kDa) and highly expressed in tumor cells [7]. In contrast to a potential oncogenic role of HAS enzymes in carcinogenesis, HAS3 under-expression was a poor prognositic marker for bladder cancer [15] and the promoter methylation of HAS3 was recently proposed to regulate hyaluronan production in pancreatic cancer [16]. Our data support an important role of HAS3-mediated short-chain HA for providing a favorable environment for oral carcinogenesis
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