Hypoxic regulation of plasminogen activator inhibitor‐1 expression in human buccal mucosa fibroblasts stimulated with arecoline

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. Method 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 ( BMF s) 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 BMF s ( 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). Conclusion 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.