Fang Chih-Yuan, Chen Szu-Han, Huang Chun-Chung, Liao Yi-Wen, Chao Shih-Chi, Yu Cheng-Chia
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan.
Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei 116, Taiwan.
Pharmaceuticals (Basel). 2022 Jul 5;15(7):833. doi: 10.3390/ph15070833.
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.
口腔黏膜下纤维化（OSF）是一种慢性纤维化重塑疾病，可进展为口腔癌。然而，目前仍缺乏针对OSF的有效临床诊断和治疗方法。本研究调查了岩藻多糖对口腔纤维化的抗纤维化作用。为了评估纤维化能力（肌成纤维细胞活性），我们分别使用患者来源的正常和纤维化颊黏膜下成纤维细胞（分别为BMF和fBMF）进行了伤口愈合、Transwell迁移和胶原收缩试验。进行了RNA测序、双荧光素酶报告基因和RNA免疫沉淀芯片试验，以确定非编码RNA的临床意义和分子机制。岩藻多糖抑制了fBMF中的肌成纤维细胞活性并抑制了MEG3。MEG3在OSF组织中过表达，且与肌成纤维细胞标志物呈正相关。敲低MEG3可显著抑制肌成纤维细胞活性，通过抑制miR-181a和过表达Egr1可使其恢复。荧光素酶报告基因和RIP试验结果证实，MEG3作为一种竞争性内源RNA（ceRNA）发挥作用，可直接靶向miR-181a，从而防止miR-181a介导的Egr1翻译抑制。本研究表明，MEG3通过靶向miR-181a/Egr1对OSF发挥促纤维化作用。因此，通过靶向MEG3的过表达给予岩藻多糖可能是一种潜在的OSF治疗策略。
