Fucoidan-Mediated Inhibition of Fibrotic Properties in Oral Submucous Fibrosis via the MEG3/miR-181a/Egr1 Axis

Abstract

Oral submucous fibrosis (OSF) is a chronic fibrotic remodeling disease that can progress to oral cancer. However, efficient clinical diagnosis and treatment methods for OSF are still lacking. This study investigated the anti-fibrotic effect of fucoidan on oral fibrosis. To evaluate the fibrotic ability (myofibroblast activities), we performed wound-healing, Transwell migration, and collagen contraction assays by using patient-derived normal and fibrotic buccal submucous fibroblasts (BMFs and fBMFs, respectively). RNA-sequencing and dual-luciferase reporter and RNA immunoprecipitation chip assays were performed to identify the clinical significance and molecular mechanism of non-coding RNAs. Fucoidan suppressed the myofibroblast activities and inhibited the MEG3 in fBMFs. MEG3 was overexpressed in the OSF tissue and was positively associated with myofibroblast markers. Knockdown of MEG3 markedly inhibited myofibroblast activities, which were restored by inhibiting miR-181a and overexpressing Egr1. The results from luciferase reporter and RIP assays confirmed that MEG3 functioned as a competing endogenous RNA (ceRNA) and could directly target miR-181a, thereby preventing the miR-181a-mediated translational repression of Egr1. This study demonstrated that MEG3 exerts a profibrotic effect on OSF by targeting miR-181a/Egr1. Therefore, the administration of fucoidan may serve as a potential therapeutic strategy for OSF by targeting the overexpression of MEG3.

Targeting histone deacetylase 9 represses fibrogenic phenotypes in buccal mucosal fibroblasts with arecoline stimulation

“… 36 Therefore, in this study, we only stimulated BMFs with arecoline for 24 h, which has been reported in our previous studies to be sufficient for inducing the pro-fibrogenic phenotypes, such as increased α-SMA expression and collagen gel contraction ability. 30 , 37 Moreover, the arecoline-induced transcriptome profile of BMFs reported in a recent study supports our findings, indicating that low-dose arecoline-induced differentially expressed genes in BMFs were involved in ECM remodeling. 32 However, this is a relatively short duration compared to the OSF pathogenesis progression that may not reflect the potential long-term consequences of arecoline.…”

“…Our previous study found a significant role of early growth response protein 1 (Egr-1) in promoting OSF progression. 30 The Egr-1 overexpression was controlled by non-coding mediated epigenetics regulation, promoting pro-fibrogenic properties and resulting in the fibroblast-to-myofibroblasts transformation. Consistent with our works, Li et al.…”

Jiawei Danxuan Koukang Alleviates Arecoline Induced Oral Mucosal Lesions: Network Pharmacology and the Combined Ultra-High Performance Liquid Chromatography (UPLC) and Mass Spectrometry (MS)

“… 6 At present, there is a lack of effective clinical diagnosis and treatment of OSF, most of which focus on reducing inflammation and improving oral opening to improve patients’ quality of life. 7 The expression of Notch was significantly upregulated in OSF tissues and TGF-β1-induced buccal mucosal fibroblasts. 8 NOTCH1 was identified as an independent prognostic factor for overall survival of early oral squamous cell carcinoma (OSCC).…”

α-Mangostin Inhibits the Activation of Myofibroblasts via Downregulation of Linc-ROR-Mediated TGFB1/Smad Signaling

“…LincRoR has been shown to modulate cancer progression via interaction with microRNA-145 [ 47 ], and microRNA-145-5p was shown to ameliorate hypertrophic scar through suppression of myofibroblast activation and reduction of Smad2/3 [ 53 ]. Furthermore, microRNA-181a has been demonstrated as an anti-fibrotic factor in fBMFs [ 54 ], and participated in TGF-β-induced EMT in hepatocytes [ 55 ]. As for miR-205, it was found to attenuate the angiotensin II-induced fibrosis in vivo and myofibroblast activation in atrial fibroblasts [ 56 ].…”