表观遗传调控在胰腺癌转移中扮演关键角色。RNA腺嘌呤甲基化修饰（m6A）是一种新发现的表观调控机制，其在恶性肿瘤中的作用是目前的研究热点。我们前期证实调控m6A修饰的主要分子METTL3其在胰腺癌的表达水平与患者预后密切相关，进一步芯片筛选METTL3下游甲基化修饰的靶分子发现miR-205可能是潜在靶点，而miR-205是调控促肿瘤上皮间质化转录因子Zeb-1的主要上游分子。基于此，我们推测METTL3可以通过诱导miR-205发生m6A修饰来调控miR-205/Zeb-1信号作用进而影响胰腺癌转移。本项目拟从临床样本为切入点，借助多种动物模型来明确METTL3对胰腺癌转移的作用，并通过体外实验探讨miR-205/Zeb-1介导METTL3调控转移的“桥梁”作用。该课题首次探讨METTL3介导的m6A修饰对胰腺癌转移的影响，可能为胰腺癌的诊治提供新的策略。

Epigenetic regulation plays a crucial role in pancreatic cancer metastasis. Modification of RNA by methylation at adenosine (m6A) constitutes a novel regulatory mechanism at epigenetic level. This molecular mechanism is under intense study in malignancy. Our preliminary results showed that METTL3, a critical factor in m6A modification, positively correlated with overall survival of pancreatic cancer patients. Further screening of its downstream molecules revealed miR-205 as a potential target. Importantly, miR-205 is responsible for regulation of Zeb-1, which is associated with invasion and metastasis of pancreatic cancer. Accordingly, we postulate that METTL3 regulates pancreatic cancer progression and metastasis through modulating miR-205 methylation and downstream Zeb-1. This project plans to initially interrogate the clinical significance of METTL3. Then, the role of METTL3 in metastasis is determined by in vitro functional assay and in vivo animal experiments. Finally, the mechanism of miR-205/Zeb-1 in mediating the effect of METTL3 and m6A modification is explored. This study for the first time evaluates the impact of m6A modification mediated by METTL3 in pancreatic cancer metastasis and is expected to provide new clue for therapeutic strategy.