Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa

Epithelial–mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT‐inducer Slug in the progression of precancerous oral submucous fibrosis (OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline‐induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E‐box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline‐induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen. In normal BMFs, arecoline stimulation will elevate the expression of Slug, which directly binds to the promotor of type I collagen, leading to increased collagen deposition and myofibroblasts transdifferentiation. In fibrotic BMFs, inhibition of Slug will reduce the expression of the myofibroblast marker, α‐SMA, and the myofibroblast activities as well as downregulate the ECM accumulation, which may relieve the fibrotic condition.