N6-Methyladenosine (m6A) 表观遗传修饰酶METTL3对食管癌的调控及机理研究

Esophageal cancer is one of the most deadly cancers because of its aggressiveness and poor survival rate. The causes of esophageal cancer are heterogeneous and still not fully understood. Recent advances in mRNA epitranscriptomics revealed that messenger RNA (mRNA) is not only the “messenger” of the genetic material DNA, but also a critical “determiner” of gene expression. mRNA modifications such as N6-Methyladenosine (m6A) play important roles in gene expression regulation. Most importantly, the mis-regulated m6A modification can cause aberrant oncogene expression and promote tumor growth and invasion. Our preliminary study revealed that the m6A RNA methyltransferase METTL3 is significantly up-regulated in esophageal cancer samples and associated with poor patient survival. Therefore, we propose to study the correlation between METTL3 expression/m6A level and esophageal cancer progression, to identify the upstream factors that promote the aberrant METTL3 expression in esophageal cancer, and to determine role of METTL3-mediated m6A modification in esophageal cancer progression and the underlying molecular mechanisms. We seek to identify the critical METTL3 downstream oncogenes/tumor suppressors in esophageal cancer and explore the role of m6A mRNA modification and METTL3 as diagnostic markers and therapeutic targets for esophageal cancers. Completion of this project will identify novel RNA epigenetic mechanisms in regulation of esophageal cancer and provide new insights for the esophageal cancer diagnostics and treatment.

食管癌是一种危害人类健康的重大疾病，具有极强的侵袭性、非常高的死亡率和复杂的生成机理。最新研究发现，mRNA不仅仅只是DNA的信使，发生在mRNA上的表观遗传修饰如m6A等对基因表达具有重要调控作用，并且m6A修饰异常可以导致癌基因表达异常和促进肿瘤细胞生长侵袭。我们前期研究发现m6A修饰酶METTL3在临床食管癌样品中显著高表达并且METTL3表达水平与病人存活时间成反关联，因此我们提出METTL3是调控食管癌生长发展的重要癌基因的假说。本课题将研究METTL3和m6A修饰水平与食管癌恶性程度的关联，鉴定食管癌中调控METTL3异常表达的上游因子，探讨METTL3及m6A修饰异常在食管癌生长侵袭过程中的作用，鉴定受METTL3修饰调控的下游关键癌基因或者抑癌基因并研究相关的分子生物学机理。研究结果将揭示食管癌生长发展的新的RNA表观遗传机制，对食管癌的诊断和治疗具有重要意义。

食管癌（Esophageal Cancer，EC）具有极强的侵袭性和非常高的死亡率，是危害人类健康的重大疾病，总体 5 年生存率只有 15％到 25％。研究食管癌恶性发展的机制对食管癌的诊断治疗具有重要意义。最新研究发现，mRNA不仅仅只是DNA的信使，发生在mRNA上的表观遗传修饰如m6A等对基因表达具有重要调控作用，并且m6A修饰异常可以导致癌基因表达异常和促进肿瘤细胞生长侵袭。本课题将研究METTL3和m6A修饰水平与食管癌恶性程度的关联，鉴定食管癌中调控METTL3异常表达的上游因子，探讨METTL3及m6A修饰异常在食管癌生长侵袭过程中的作用，鉴定受METTL3修饰调控的下游关键癌基因或者抑癌基因并研究相关的分子生物学机理。..在本课题的资助下，申请人课题组阐明了METTL3蛋白表达与食管癌的肿瘤分期、转移、 复发等临床指标的关联, 揭示METTL3在食管癌中高表达并且METTL3的表达状况与病人的临床症状和表型存在显著关联，METTL3高表达得食管癌病人得生存显著变低，说明METTL3是食管癌恶性进展的重要分子靶标。在功能学方面，课题组利用多种体外方法阐明了敲低METTL3抑制食管癌细胞系的生长增殖侵袭，并利用METTL3的条件性敲除和转基因小鼠的flox小鼠的食管癌模型，揭示METTL3在食管癌中起着癌基因的重要功能。在机理学研究方面，通过利用m6A MeRIP-Seq，转录组学和翻译组学分析方法，鉴定NOTCH 信号通路为食管癌中受m6A修饰调控的关键下游mRNA，阐明了METTL3调控食管癌恶性发展的功能和机制。相关研究结果发表在Mol Cell, Mol Ther, Mol Ther-Nucl Acids等杂志，揭示了食管癌生长发展的新的RNA表观遗传机制，对食管癌的诊断和治疗具有重要意义。