Abstract
Oral submucous fibrosis (OSF), regarded as a precancerous condition, is characterized by juxta-epithelial inflammatory reaction followed by fibro-elastic change in the lamina properia and epithelial atrophy. The pathologic mechanisms of OSF still need to be further clarified. In the study, we investigated the functional expression of SSEA-4, which is a well-known stemness marker, in myofibroblast activity and the clinical significance in OSF tissues. The expression of SSEA-4 in OSF was evaluated by immunohistochemical staining. Functional analysis of SSEA-4 on myofibroblast activity of OSF was achieved by lentiviral silencing ST3GAL2. Immunohisitochemistry demonstrated that SSEA-4 expression was significantly higher expression in areca quid chewing-associated OSF tissues than those of normal oral mucosa tissues. From flow cytometry analysis, arecoline dose-dependently activated SSEA-4 expression in primary human normal buccal mucosal fibroblasts (BMFs). Sorted SSEA-4-positive cells from fibrotic BMFs (fBMFs) have higher colony-forming unit, collagen gel contraction, and α-smooth muscle actin (α-SMA) expression than SSEA-4-negative subset. Knockdown of ST3GAL2 in fBMFs suppressed SSEA-4 expression, collagen contraction, migration, invasiveness, and wound healing capability. Consistently, silencing ST3GAL2 was found to repress arecoline-induced myofibroblast activity in BMFs. The study highlights SSEA-4 as a critical marker for therapeutic intervention to mediate myofibroblast transdifferentiation in areca quid chewing-associated OSF.
Highlights
Sorted SSEA-4+ fibroblasts subpopulation from idiopathic pulmonary fibrosis could display mesenchymal stem cells and fibrogenic characteristics[18]
To further examine the effect of arecoline, the major areca nut alkaloid, on SSEA-4 expression in buccal mucosal fibroblasts (BMFs), BMFs treated with arecoline and the levels of SSEA-4 were measured by flow cytometry analysis
Mounting evidences have demonstrated that the dys-regulation of stemness marker expression contributes to the pathogenesis of diseases, especially its roles in tumorigenesis[20,21]
Summary
Sorted SSEA-4+ fibroblasts subpopulation from idiopathic pulmonary fibrosis could display mesenchymal stem cells and fibrogenic characteristics[18]. The functional role of SSEA-4 in OSF still remains unknown. We first demonstrate that SSEA-4 expression is significantly increased in areca quid chewing-associated OSF tissues. Arecoline could induce SSEA-4 expression in BMFs. Knockdown of SSEA-4 synthesis could abolish myofibroblast activity in fibrotic BMFs (fBMFs). Targeting SSEA-4 may be a potential therapeutic approach to suppress myofibroblast transdifferentiation for the pathogenesis of areca quid chewing-associated OSF
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