LINC00084/miR-204/ZEB1 Axis Mediates Myofibroblastic Differentiation Activity in Fibrotic Buccal Mucosa Fibroblasts: Therapeutic Target for Oral Submucous Fibrosis.

Yu-Hsien Lee,Pei-Ling Hsieh,Yi-Wen Liao,Ming-Yi Lu,Cheng-Chia Yu

doi:10.3390/jpm11080707

Abstract

Oral submucosal fibrosis (OSF) is a precancerous condition in the oral cavity and areca nut consumption has been regarded as one of the etiologic factors implicated in the development of OSF via persistent activation of buccal mucosal fibroblasts (BMFs). It has been previously reported that an epithelial to mesenchymal transition (EMT) factor, ZEB1, mediated the areca nut-associated myofibroblast transdifferentiation. In the current study, we aimed to elucidate how areca nut affected non-coding RNAs and the subsequent myofibroblast activation via ZEB1. We found that long non-coding RNA LINC00084 was elicited in the BMFs treated with arecoline, a major alkaloid of areca nut, and silencing LINC00084 prevented the arecoline-induced activities (such as collagen gel contraction, migration, and wound healing capacities). The upregulation of LINC00084 was also observed in the OSF tissues and fibrotic BMFs (fBMFs), and positively correlated with several fibrosis factors. Moreover, we showed knockdown of LINC00084 markedly suppressed the myofibroblast features in fBMFs, including myofibroblast phenotypes and marker expression. The results from the luciferase reporter assay confirmed that LINC00084 acted as a sponge of miR-204 and miR-204 inhibited ZEB1 by directly interacting with it. Altogether, these findings suggested that the constant irritation of arecoline may result in upregulation of LINC00084 in BMFs, which increased the ZEB1 expression by sequestering miR-204 to induce myofibroblast transdifferentiation.

Highlights

As one of the potentially malignant oral disorders, oral submucous fibrosis (OSF) is a chronic inflammatory condition in the oral cavity characterized by the excessive deposition of extracellular matrix (ECM) components, such as collagen
It has been indicated that the ingredients of areca nut elicit tissue inflammation, myofibroblast differentiation, and alteration of ECM turnover through modulation of numerous molecular signaling such as transforming growth factor-beta 1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitors of metalloproteinases (TIMPs), and metalloproteinases (MMPs) [7]
LINC00084 was implicated in the arecoline-induced myofibroblast activation, we examined the relative expression of LINC00084 in two normal buccal mucosal fibroblasts (BMFs) following treatment of various concentrations of arecoline

Summary

Introduction

As one of the potentially malignant oral disorders, oral submucous fibrosis (OSF) is a chronic inflammatory condition in the oral cavity characterized by the excessive deposition of extracellular matrix (ECM) components, such as collagen. Various studies have shown that an increase in myofibroblasts is implicated in the severity and progression of OSF and oral cancer [5,6]. It has been indicated that the ingredients of areca nut elicit tissue inflammation, myofibroblast differentiation, and alteration of ECM turnover through modulation of numerous molecular signaling such as transforming growth factor-beta 1 (TGF-β1), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitors of metalloproteinases (TIMPs), and metalloproteinases (MMPs) [7]. Several studies have shown that the areca nut-associated inflammatory cytokines induce cells to undergo epithelial to mesenchymal transition (EMT) [8,9], a potential driving force of myofibroblast transdifferentiation [10]. A growing body of research suggests non-coding RNAs play integral roles in the activation of myofibroblasts

Objectives

Methods

Results

Discussion

Conclusion