title: Hypoxic regulation of plasminogen activator inhibitor-1 expression in human buccal mucosa fibroblasts stimulated with arecoline.
abstract: BACKGROUND
  Oral submucous fibrosis (OSF) is regarded as a pre-cancerous condition with fibrosis in oral subepithelial connective tissue. Hypoxia-inducible factor (HIF)-1α regulates a wide variety of profibrogenic genes, which are closely associated with tissue fibrosis. The aim of this study was to compare HIF-1α expression in normal buccal mucosa tissues and OSF specimens and further explore the potential mechanisms that may lead to the induction of HIF-1α expression.
  
  
  METHODS
  Twenty-five OSF specimens and six normal buccal mucosa were examined by immunohistochemistry. The expression of HIF-1α from fibroblasts cultured from OSF and normal buccal mucosa was measured by Western blot. Arecoline, a major areca nut alkaloid, was challenged to normal buccal mucosa fibroblasts (BMFs) to elucidate whether HIF-1α expression could affect by arecoline. In addition, the effects of arecoline on plasminogen activator inhibitor (PAI)-1 expression were evaluated in environmental hypoxia.
  
  
  RESULTS
  HIF-1α expression was significantly higher in OSF specimens and expressed mainly by fibroblasts, epithelial cells, and inflammatory cells. Fibroblasts derived from OSF were found to exhibit higher HIF-1α protein expression than BMFs (P < 0.05). Arecoline was found to upregulate HIF-1α protein in a dose-dependent manner (P < 0.05). Hypoxia increased arecoline-induced PAI-1 protein expression than normoxic conditions (P < 0.05).
  
  
  CONCLUSIONS
  These results suggest that HIF-1α expression is significantly upregulated in OSF tissues from areca quid chewers, implying a potential role as a biomarker for local tissue hypoxia. The activation of HIF-1α may promote fibrogenesis by an increase of PAI-1 expression and a subsequent elevation of extracellular matrix production in oral submucosa leading to fibrosis.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|Department of Oral Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chung-Hung
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.|School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D001115:Arecoline / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D003238:Connective Tissue / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D008297:Male; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009914:Oral Submucous Fibrosis / Q000188:drug therapy / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D001115:Arecoline
keywords: arecoline; buccal mucosa fibroblasts; hypoxia-inducible factor-1α; oral submucous fibrosis; plasminogen activator inhibitor-1