RRC ID 65874
Author Kuo YZ, Fang WY, Huang CC, Tsai ST, Wang YC, Yang CL, Wu LW.
Title Hyaluronan synthase 3 mediated oncogenic action through forming inter-regulation loop with tumor necrosis factor alpha in oral cancer.
Journal Oncotarget
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.
Volume 8(9)
Pages 15563-15583
Published 2017-2-28
DOI 10.18632/oncotarget.14697
PII 14697
PMID 28107185
PMC PMC5362506
MeSH Animals Blotting, Western Carcinogenesis / genetics Cell Line, Tumor Cell Movement / genetics Cells, Cultured Chemokine CCL2 / genetics Chemokine CCL2 / metabolism Female Gene Expression Regulation, Neoplastic* Glucuronosyltransferase / genetics* Glucuronosyltransferase / metabolism Humans Hyaluronan Synthases Hyaluronic Acid / metabolism Kaplan-Meier Estimate Male Mice, Inbred BALB C Middle Aged Mouth Neoplasms / genetics* Mouth Neoplasms / metabolism Mouth Neoplasms / pathology NF-kappa B / genetics NF-kappa B / metabolism RNA Interference Reverse Transcriptase Polymerase Chain Reaction Transplantation, Heterologous Tumor Necrosis Factor-alpha / genetics* Tumor Necrosis Factor-alpha / metabolism
IF 5.168
Human and Animal Cells SAS(RCB1974)