Slug mediates myofibroblastic differentiation to promote fibrogenesis in buccal mucosa

Abstract

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.

Role of the arecoline/YAP1/BMP4 pathway in promoting endothelial‐mesenchymal transition in oral submucous fibrosis

“…Epithelial‐mesenchymal transition (EMT) is considered to be an important mechanism of OSF; EMT is associated with an increase in extracellular matrix (ECM) secretion and fibroblast activation. An increase in EMT‐associated factors is widely observed during the development of fibrotic lesions.…”

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy

“…Chewing betel nut is the main cause of OSF [25][26][27][28]. The histopathology of OSF comprises various epithelial alterations, rete-peg shapes, and subepithelial deposition of dense bands of collagen fibers.…”

“…A shift in epithelial compliance in response to increased connective tissue fibrosis favors the initiation of carcinomatous processes such as epithelial-mesenchymal transition (EMT) [31,32]. The most common initial symptoms of OSF are ulceration, xerostomia, a burning sensation, and limited ability to open the mouth [27,33]. These effects interfere with the daily life of the patient and may lead to complications.…”

“…EMT may be involved in the malignant transformation of OSF. EMT activators participate in betel nut associated OSF [27,55,73,74]. EMT-inducing transcription factors such as snail, slug, and twist are involved in the pathogenesis of betel nut related OSF.…”

“…EMT-inducing transcription factors such as snail, slug, and twist are involved in the pathogenesis of betel nut related OSF. They initiate and facilitate the acquisition of a mesenchymal phenotype by repressing E-cadherin [27,73,75]. Zinc finger E-box binding homeobox 1 (ZEB1), another EMT-inducing transcription factor, is also implicated in betel nut associated OSF pathogenesis because it activates the α-SMA promoter [74].…”