NAT10介导的lncRNA MALAT1-ac4C乙酰化修饰通过Wnt/β-catenin通路促进肺癌侵袭转移的作用和机制研究

侵袭转移严重影响肺癌预后。RNA-ac4C乙酰化修饰与肿瘤发生发展相关，但其影响肺癌的机制尚不清楚。NAT10是目前已知的人类唯一的RNA-ac4C乙酰化酶。我们前期预实验发现NAT10在肺癌组织和细胞株中高表达，可促进侵袭转移恶性表型；NAT10敲除显著降低lnc-MALAT1-ac4C乙酰化修饰水平。MALAT1可激活Wnt/β-catenin通路促进肿瘤进展，我们进一步实验发现NAT10敲除抑制了Wnt/β-catenin通路标志分子的表达。因此合理推测：NAT10介导lnc-MALAT1-ac4C通过Wnt/β-catenin通路促进肺癌侵袭转移。本课题拟应用acRIP-seq、CRISPR/Cas9、acRIP-qPCR 以及LC-MS等技术，并结合临床标本和动物实验，依次从组织、细胞、分子及动物四个层次开展实验来验证本课题的科学假说。本课题的顺利实施，将为肺癌的防治提供新靶点。

Invasion and metastasis seriously affect the prognosis of lung cancer. The acetylation of RNA-ac4C is associated with tumorigenesis and development. However, the relationship between RNA-ac4C acetylation disorder and lung cancer is not clear. NAT10 is the only known RNA-ac4C acetylase in humans. We found that high expression of NAT10 in lung cancer tissues and cell lines could promote the malignant phenotype of invasion and metastasis in our previous experiments, and NAT10 knock-out significantly reduced the level of lnc-MALAT1-ac4C acetylation modification. MALAT1 can activate Wnt/β-catenin pathway and promote tumor progression. We found that NAT10 knock-out inhibited the expression of Wnt/β-catenin pathway marker in the further experiment. Therefore, it is reasonable to speculate that NAT10 mediates lnc-MALAT1-ac4C to promote the invasion and metastasis of lung cancer through Wnt/β-catenin pathway. In order to test the scientific hypothesis, we will use the technology of acRIP-seq, CRISPR/Cas9, acRIP-qPCR and LC-MS, and combine with clinical samples and animal experiments. The successful implementation of this project will provide a new target for the prevention and treatment of lung cancer.