RNA结合蛋白(RBP)通过m6A表观遗传修饰影响RNA代谢，进而调控细胞功能，是RBP-RNA相互作用领域新突破(Nat Immunol,2017)。申请人前期发现DDX5和m6A修饰酶METTL3在口腔白斑病(OLK)中高表达，与异常增生正相关；结合申请人既往OLK表观遗传机制研究，我们假定DDX5通过METTL3对增殖相关RNA进行m6A修饰，促进RNA出核翻译而导致细胞增殖失衡。为验证此假说，拟首先在大样本OLK队列中进一步验证DDX5与异常增生程度的关系，并在细胞水平考察其在调控口腔黏膜上皮异常增殖中的作用；然后以METTL3为切入点，研究DDX5调控OLK上皮异常增殖的分子机制；最后通过基因编辑小鼠4NQO饮水诱导口腔黏膜异常增生模型，从遗传学上印证体外研究结果。研究不仅有助于阐明m6A修饰影响RBP-RNA相互作用在OLK衍进中的效应及新机制，也为逆转其增殖表型提供新思路。

A breakthrough was made recently in RNA-binding protein (RBP)-RNA interactions. RBP could regulate cell functions by m6A epigenetic modifications affecting RNA metabolism (Nat Immunol, 2017). Previous research has revealed that DDX5 and m6A methylase METTL3 were highly expressed in oral leukoplakia (OLK) tissues, and were positively correlated with degrees of abnormal proliferation. So the hypothesis was presented that DDX5 promotes cell proliferation by enhancing m6A-methylated proliferative transcripts exported from the nucleus, which is related to METTL3. To confirm that, firstly, expression level of DDX5 will be tested in a large-sample OLK cohort to verify the correlation between high expression of DDX5 in OLK and degrees of abnormal proliferation, its role in regulating abnormal proliferation was also investigated at the cellular level. Secondly, based on METTL3, the molecular mechanism of DDX5 regulating OLK abnormal proliferation will be studied. Finally, all those findings will be further confirmed by 4-nitroquinoline-1-oxide (4NQO) model of K5-cre; DDX5KI/KI mice and K5-cre; DDX5-/- mice. That can not only help us clarify the regulating effect and mechanism of RNA-binding proteins DDX5 in the development of oral leukoplakia, but also provide a new strategy for prevention and treatment of oral potentially malignant disorders.