HIF-1α Expression in Areca Quid Chewing-associated Oral Submucous Fibrosis

Objective: Oral submucous fibrosis (OSF) is regarded as a precancerous condition, and is a chronic insidious disease of oral subepithelial connective tissue. Areca quid chewing is a major risk factor of OSF. 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:  The expression of HIF-1α from fibroblasts cultured from OSF and normal buccal mucosa were by using 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. Result:  Fibroblasts derived from OSF were found to exhibit higher HIF-1α expression than BMFs in protein levels (p<0.05). In addition, the upregulation of HIF-1α protein expression was found in BMFs stimulated by arecoline (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 and arecoline may be responsible for the enhanced HIF-1α expression in vivo. Moreover, the activation of HIF-1α may promote fibrogenesis by an increase of PAI-1 expression and a subsequent elevation of extracellular matrix production in buccal mucosa leading to OSF. This study was supported by NSC100-2632-B-040-001-MY3.