Abstract
Oral submucosal fibrosis (OSF) is a premalignant disorder of the oral cavity, and areca nut chewing is known to be a major etiological factor that could induce epithelial to mesenchymal transition (EMT) and activate buccal mucosal fibroblasts (BMFs). However, this detailed mechanism is not fully understood. In this study, we showed that the upregulation of Snail in OSF samples and fibrotic BMFs (fBMFs) may result from constant irritation by arecoline, a major alkaloid of the areca nut. The elevation of Snail triggered myofibroblast transdifferentiation and was crucial to the persistent activation of fBMFs. Meanwhile, Snail increased the expression of numerous fibrosis factors (e.g., α-SMA and collagen I) as well as IL-6. Results from bioinformatics software and a luciferase-based reporter assay revealed that IL-6 was a direct target of Snail. Moreover, IL-6 in BMFs was found to further increase the expression of Snail and mediate Snail-induced myofibroblast activation. These findings suggested that there was a positive loop between Snail and IL-6 to regulate the areca nut-associated myofibroblast transdifferentiation, which implied that the blockage of Snail may serve as a favorable therapeutic strategy for OSF treatment.
Highlights
Oral submucosal fibrosis (OSF) is an insidious inflammatory condition which accompanies the excess fibrous connective tissue which accumulates in the oral cavity
Results from the RT-PCR confirmed that the relative expression of Snail in OSF tissues (Figure 1B) and fibrotic buccal mucosal fibroblasts (BMF) (fBMFs) derived from OSF specimens (Figure 1C) were increased
Our results showed that the gene (Figure 1D) and protein (Figure 1E and Figure S1) expression levels of Snail in BMFs were dose-dependently elevated in response to the arecoline treatment
Summary
Oral submucosal fibrosis (OSF) is an insidious inflammatory condition which accompanies the excess fibrous connective tissue which accumulates in the oral cavity. It has been suggested that OSF is one of the most potentially malignant oral disorders [1] and around 10% of OSF cases may transform into malignancy, oral squamous cell carcinoma (OSCC) [2,3]. An epidemiological study has revealed that the habit of areca nut chewing is a major etiology [4], and areca nut constituents have been known to increase pro-inflammatory cytokines, such as transforming growth factor (TGF)-β [5]. It has been indicated that TGF-β stimulates the activation of pro-collagen genes and the elevation of collagenase inhibitors, which disturbs the collagen metabolism in OSF [6]. TGF-β has been shown to regulate the differentiation of oral fibroblasts into myofibroblasts [7]
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