title: Elevation of S100A4 expression in buccal mucosal fibroblasts by arecoline: involvement in the pathogenesis of oral submucous fibrosis.
abstract: BACKGROUND
  S100A4, a member of the calcium-binding proteins, is dramatically elevated in a variety of fibrotic diseases. Areca quid chewing is the most important etiological factor in the pathogenesis of oral submucous fibrosis (OSF). OSF has been considered as a pre-cancerous condition of oral mucosa. The aim of this study was to determine the critical role of S100A4 expression in the pathogenesis of OSF both in vitro and in vivo.
  
  
  RESULTS
  Thirty OSF tissues from areca quid chewers and ten normal buccal mucosa samples without areca quid chewing were analyzed by using immunohistochemistry for S100A4 expression in vivo. Collagen gel contraction capability and expression of tissue inhibitor of metalloproteinases 1 (TIMP1)/MMP9 in arecoline-stimulated BMFs with S100A4 knockdown was presented in vitro. Initially, S100A4 expression was higher in areca quid chewing-associated OSF specimens than normal buccal mucosa specimens (p = 0.001). Arecoline, a major areca nut alkaloid, led to dose- and time-dependent elevation of S100A4 expression in normal buccal mucosa fibroblasts BMFs (p<0.05). The additions of pharmacological agents rapamycin (mTOR inhibitor), PD98059 (ERK inhibitor), and Bay117082 (NF-κB inhibitor) were found to inhibit arecoline-induced S100A4 expression (p<0.05) in BMFs. Down-regulation of S100A4 by lentiviral infection significantly reversed arecoline-induced collagen gel contraction and TIMP1/MMP9 expression.
  
  
  CONCLUSIONS
  These results suggest that S100A4 expression is significantly up-regulated in OSF specimens. Arecoline-induced S100A4 expression was down-regulated by rapamycin, PD98059, and Bay117082. Targeting S100A4 might be a potential therapeutic target for OSF through TIMP1/MMP9 down-regulation.
authors: Institute of Oral Science, Chung Shan Medical University, Taichung, Taiwan.
authors: Cheng-Chia
authors: CC
authors: Yu
authors: Chung-Hung
authors: CH
authors: Tsai
authors: Hsin-I
authors: HI
authors: Hsu
authors: Yu-Chao
authors: YC
authors: Chang
mesh_terms: D001115:Arecoline / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009914:Oral Submucous Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C077591:S100A4 protein, human; D001115:Arecoline; D003094:Collagen; D058570:TOR Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9
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