title: Role of Areca Nut Induced TGF-β and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis.
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.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Ila
authors.initials: I
authors.lastname: Pant
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Department of Oral and Maxillofacial Surgery, D.A. Pandu Memorial-R.V. Dental College and Hospital, Bangalore, Karnataka, India.
authors.forename: Somanahalli Girish
authors.initials: SG
authors.lastname: Rao
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Paturu
authors.initials: P
authors.lastname: Kondaiah
mesh_terms: D001114:Areca / Q000737:chemistry*; D016000:Cluster Analysis; D003094:Collagen / Q000737:chemistry; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D015894:Genome, Human; D005881:Gingiva / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D009754:Nuts / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D009914:Oral Submucous Fibrosis / Q000139:chemically induced* / Q000473:pathology*; D011230:Precancerous Conditions / Q000473:pathology; D015398:Signal Transduction; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta; D003094:Collagen