Research Papers:
Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer
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Abstract
Yi-Zih Kuo1, Wei-Yu Fang1, Cheng-Chih Huang2, Sen-Tien Tsai2,3, Yi-Ching Wang4, Chih-Li Yang5, Li-Wha Wu1,5,6
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C
2Department of Otolaryngology, National Cheng Kung University Hospital, Tainan 70428, Taiwan, R.O.C
3Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan 70428, Taiwan, R.O.C
4Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C
5Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C
6Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C.
Correspondence to:
Li-Wha Wu, email: [email protected]
Sen-Tien Tsai, email: [email protected]
Keywords: hyaluronan, HAS3, oral cancer, TNF-α, MCP-1
Received: July 20, 2016 Accepted: December 27, 2016 Published: January 17, 2017
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.
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