lncRNA MALAT1/miR-203调控FAK介导TGF-β通路引起口腔黏膜下纤维化 的机制研究

Oral submucous fibrosis (OSF) is a chronic, cancerous disease. However, there is very limited knowledge on and its pathogenic molecular mechanism is still unclear. Areca nut causes OSF through physicochemical factors, and miRNA plays an important role in OSF development. The miRNA microarray and qPCR showed that the expression of miR-203 was significantly decreased in OSF, and the therapeutic drug intervention could reverse it. Myofibroblasts (MFB) are present in OSF, whereas TGF-β induces MFB formation by FAK. Our research group predicted that lncRNA MALAT1 and miR-203, which play an important role in TGF-β-mediated fibrosis, have binding sites, while miR-203 and FAK can bind to each other. Therefore, the Based on this hypothesis that: arecoline stimulates fibroblasts, which alters the expression of MALAT1 and miR-203 and regulates FAK-mediated TGF-β pathway to promote MFB conversion leading to OSF was given. This project intends to clarify the molecular mechanism of MALAT1/miR-203 after the fibroblasts stimulated by arecoline-stimulated fibroblasts through in vitro and in vivo studies and , and to investigateclarify its potential to bevalue as a molecular marker and therapeutic target. This work could, and to provide new ideas and experimental basis for the prevention and treatment of OSF.

口腔黏膜下纤维性化（OSF）是一种慢性、具有癌变倾向的疾病，其发生发展与咀嚼槟榔密切相关，但致病机制尚不明确。课题组通过miRNA芯片及qPCR发现miR-203在OSF中表达显著下降，且治疗药物干预可使其在槟榔碱诱导建立的OSF细胞模型中表达明显逆转。OSF中存在肌成纤维细胞（MFB），而TGF-β通过FAK诱导MFB形成。课题组前期预测在TGF-β介导纤维化中起重要作用的lncRNA MALAT1与miR-203存在结合位点，而miR-203与FAK可靶向结合。据此提出假设：槟榔碱诱导成纤维细胞使MALAT1、miR-203表达改变，调控FAK介导TGF-β通路促进MFB转化从而导致OSF发生。本项目拟通过体内外研究，阐述槟榔碱诱导成纤维细胞后MALAT1/miR-203作用的分子机制，探索其作为分子标志物及治疗靶标的价值，为防治OSF提供新思路和理论基础。

口腔黏膜下纤维化（oral submucous fibrosis，OSF）是一种慢性进行性疾病，可表现为口干、进食疼痛、黏膜水泡、局部或全口黏膜苍白、出现纤维条索，进而张口受限，伸舌及吞咽困难，甚至癌变，严重影响患者的身心健康。研究表明，OSF发生发展与咀嚼槟榔行为存在密切关系。因此，阐明咀嚼槟榔引起OSF的发病机制，寻求有效的防治途径，具有重要的临床和社会意义。. 课题组前期通过芯片筛查及qPCR等实验发现，miR-203在OSF中表达显著下调，且OSF细胞模型经过治疗药物干预后miR-203明显逆转，表明miR-203在OSF发生发展过程中起重要作用，但其作用分子机制尚不明确。课题组通过软件预测发现，FAK是miR-203的靶基因。而FAK通过TGF-β1受体介导细胞因子的胞内信号传导，沉默FAK基因将阻断正常成纤维细胞转化为肌成纤维细胞。提示，miR-203通过FAK介TGF-β信号通路在OSF中起作用。综上所述，申请人在前期研究基础上提出，槟榔碱诱导成纤维细胞使 lncRNA MALAT1和miR-203的表达发生改变后，通过调控FAK介导TGF-β信号通路，诱导成纤维细胞转化为肌成纤维细胞，从而促进OSF发生发展的科学假说。. 本研究的重要结果显示lncRNA MALAT1基因沉默可以抑制经槟榔碱刺激的BMFs迁移和胶原收缩能力，提示lncRNA MALAT1可能是BMFs向肌成纤维细胞转分化的促进因子；本研究还探究了miR-203在OSF发病机制中的作用，成果表明FAK可能是miR-203的靶基因。为深层次探寻lncRNA MALAT1及miR-203的作用机制及相关的分子通路并开展靶向调控将为OSF的治疗提供新思路。. 通过本项目的研究，可明确lncRNA MALAT1/miR-203在OSF发生发展过程中的分子机制，为筛选OSF分子标志物及靶向治疗药物的开发奠定研究基础，对OSF防治工作具有潜在的应用前景和重要意义。