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

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.

Low LINC02147 expression promotes the malignant progression of oral submucous fibrosis

“…However, studies of lncRNAs in the occurrence and malignant progression of OSF are still in nascent. To date, only 8 lncRNAs have been found to be related to the pathogenesis of OSF [ 38 ], including H19 [ 39 ], LINC00084 [ 40 ], HIF1A-AS1 [ 13 ], LINC00312 [ 12 ], LINC00974 [ 11 ], HOTTIP [ 41 ], GAS5-AS1 [ 10 ] and ADAMTS9-AS2 [ 15 ]. These lncRNAs are involved in the pathogenesis of OSF mainly by regulating myofibroblast activation [ 10 – 13 , 39 – 41 ] and epithelial to mesenchymal transition (EMT) [ 40 ].…”

“…To date, only 8 lncRNAs have been found to be related to the pathogenesis of OSF [ 38 ], including H19 [ 39 ], LINC00084 [ 40 ], HIF1A-AS1 [ 13 ], LINC00312 [ 12 ], LINC00974 [ 11 ], HOTTIP [ 41 ], GAS5-AS1 [ 10 ] and ADAMTS9-AS2 [ 15 ]. These lncRNAs are involved in the pathogenesis of OSF mainly by regulating myofibroblast activation [ 10 – 13 , 39 – 41 ] and epithelial to mesenchymal transition (EMT) [ 40 ]. In addition, only ADAMTS9-AS2 has been confirmed to be associated with the malignant progression of OSF to OSCC [ 15 ].…”

Pro‐angiogenic role of ZEB1 in skin wound healing by upregulating VEGFA via microRNA‐206 suppression

“…has been revealed to contribute to liver fibrosis and oral submucosal fibrosis. 33,34 Meanwhile, fibrosis might contribute to progressive tissue scarring and organ dysfunction. 35 Therefore, more efforts should be devoted to clarify the detrimental effects of ZEB1 on skin fibrosis to wound healing process.…”

Long Non-Coding RNAs in Oral Submucous Fibrosis: Their Functional Mechanisms and Recent Research Progress

“… 95 According to Lee and colleagues, LINC00084 is up-regulated in OSF tissues and myofibroblasts generated from OSF specimens, and is favorably linked with a number of fibrotic variables. 34 Silencing LINC00084 expression has been shown to prevent arecoline-induced activities (eg, contraction and migration of collagen gel, and wound-healing capacities). LINC00084 interacts with miR-204, and prevents it from binding directly to ZEB1.…”

“…LINC00084 shows aberrantly high expression in OSF tissues and myofibroblasts. 34 The lncRNAs related to fibrosis pathogenesis mainly involve cell macromolecules (eg, chromatin, protein, RNA). 35 The role of ncRNAs (especially lncRNAs) in fibrosis is being investigated gradually, and the underlying mechanism between them and OSF must be clarified.…”