title: Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer.
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.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.
authors.forename: Yi-Zih
authors.initials: YZ
authors.lastname: Kuo
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.
authors.forename: Wei-Yu
authors.initials: WY
authors.lastname: Fang
authors.affiliation: Department of Otolaryngology, National Cheng Kung University Hospital, Tainan 70428, Taiwan, R.O.C.
authors.forename: Cheng-Chih
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Otolaryngology, National Cheng Kung University Hospital, Tainan 70428, Taiwan, R.O.C.|Department of Radiation Oncology, National Cheng Kung University Hospital, Tainan 70428, Taiwan, R.O.C.
authors.forename: Sen-Tien
authors.initials: ST
authors.lastname: Tsai
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Yang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.|Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.|Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C.
authors.forename: Li-Wha
authors.initials: LW
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases
keywords: HAS3; MCP-1; TNF-α; hyaluronan; oral cancer