METTL3介导的STAT3 m6A甲基化修饰在肝癌转移中的作用及分子机制研究

Hepatocellular carcinoma (HCC) is a common malignant tumor. Most HCC-associated mortality is related to the metastasis of malignant cancer cells. Recent evidence reveals that the dysregulation of m6A methylation of RNA is closely associated with the progression and metastasis of cancers. The RNA methylase METTL3 plays a critical function in the regulation of m6A level. STAT3 is an important oncogene that is well-studied. Our previous finding demonstrated that the m6A level of STAT3 mRNA was significantly upregulated in the highly metastatic HCC cell lines. Moreover, METTL3 was closely related to the upregulation of STAT3 mRNA m6A level and the regulation of STAT3 expression. However, whether this abnormal upregulation plays a role in HCC metastasis and the underlying mechanism remain unclear. Accordingly, this program will conduct series of studies at molecular, cell, tissue and animal levels as follows: 1) Reveal the association of m6A level of STAT3 mRNA with HCC metastasis. 2) Clarify the molecular mechanism of METTL3 modulating STAT3 expression by regulating the STAT3 mRNA m6A level, and explore the positive feedback loop of METTL3/STAT3. 3) Evaluate the effect of METTL3/STAT3 on HCC metastasis by multiple methods. Our findings will provide novel strategy and new target for the precise treatment of HCC.

肝癌是一种常见的恶性肿瘤，癌细胞转移是导致肝癌患者死亡的主要原因。近来研究表明，RNA的m6A甲基化修饰失调与癌症的发展及转移密切相关。其中，RNA甲基转移酶METTL3在m6A水平调控方面发挥了关键性作用。STAT3是一个被广泛研究的重要癌基因，我们前期研究发现，STAT3 mRNA m6A水平在高转移肝癌细胞系中显著上调，METTL3与STAT3 mRNA m6A水平异常及表达调控密切相关。然而，该水平上调在肝癌转移中的作用及其分子机制均有待揭示。本项目拟从分子、细胞、组织和动物模型等层次研究以下科学问题：1）明确STAT3 mRNA m6A水平与肝癌细胞转移的关系；2）阐明METTL3通过调控m6A水平影响STAT3表达的分子机制，并探索二者之间的正反馈调控关系；3）综合评价METTL3/STAT3正反馈环路对肝癌转移的影响。本创新发现将为肝癌的精准治疗提供新的研究策略和新靶点。

肝细胞癌（Hepatocellular carcinoma，HCC）是一种常见的恶性肿瘤，严重危害着人类生命健康。肿瘤转移是多数HCC患者死亡的主要原因，然而其转移的分子机制仍有待深入探索。目前的证据表明，METTL3介导的m6A甲基化修饰的失调与癌症进展密切相关。STAT3是一个被广泛关注的致癌转录因子，它在癌症的发生和发展中起着重要的作用。然而，METTL3和STAT3在HCC转移中的关系尚不清楚。本项目拟从分子、细胞、组织和动物模型等层次研究METTL3和STAT3在HCC转移过程中的重要作用。本项目研究发现，STAT3和METTL3在HCC组织中高表达，而且二者的表达水平呈正相关。METTL3可诱导STAT3 mRNA的m6A修饰，随后增强STAT3 mRNA翻译，上调STAT3的表达水平。同时，STAT3能够通过转录上调WTAP（甲基转移酶复合物的重要成员）促进METTL3的核定位，进而增强METTL3的甲基转移酶功能。体内和体外研究证明，METTL3和STAT3形成一个正反馈环路，促进HCC转移。我们的发现揭示了HCC转移的新机制，将为肝癌的精准治疗提供新的研究策略和新靶点。