Role of Areca Nut Induced TGF-β and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis.

Ila Pant,Neeraj Kumar,Paturu Kondaiah,Somanahalli Girish Rao,Imran Khan,Philip C Trackman

doi:10.1371/journal.pone.0129252

Ila Pant, Neeraj Kumar + Show 4 more

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https://doi.org/10.1371/journal.pone.0129252

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Abstract

Areca nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-β signaling in epithelial cells by areca nut components and also propose a role for epithelial expressed TGF-β in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of areca nut and TGF-β in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with areca nut and/or TGF-β followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and areca nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by areca nut and TGF-β treatment respectively. The expression of 413 genes in hGF cells was potentiated by areca nut and TGF-β together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with areca nut and TGF-β induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and areca nut +TGF-β treated hGF cells. In concordance, areca nut along with TGF-β enhanced fibroblast activation as demonstrated by potentiation of αSMA, γSMA and collagen gel contraction by hGF cells. Furthermore, TGF-β secreted by areca nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for areca nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF.

Highlights

Oral submucous fibrosis is prevalent in South and South East Asia [1]
As described in the introduction, areca nut has been proposed as the etiological agent for Oral Submucous fibrosis (OSF) and has been shown to influence the activation of Transforming growth factor-β (TGF-β) pathway in epithelial cells [10]
Decoding the response of fibroblasts to areca nut and TGF-β is essential to understand the molecular mechanisms in the manifestation of OSF

Summary

Introduction

Oral submucous fibrosis is prevalent in South and South East Asia [1] It is a pre-cancerous condition characterized by inflammation, epithelial atrophy and trismus of the oral cavity due to excessive extracellular matrix deposition [2,3]. The profile obtained was further compared with the transcriptome of OSF tissues and areca nut induced transcriptome in epithelial cells [6,10]. These data demonstrate the involvement of both areca nut and epithelium derived TGF-β in altering fibroblast phenotype, highlighting the importance of epithelial mesenchymal interaction in OSF

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