lncRNA CASC11调控ALKBH5介导的UBE2T mRNA m6A修饰促进肝癌发生发展的机制研究

LncRNAs play an important role in various biological processes. However, the function and molecular mechanism of lncRNA CASC11 in regulating the development of hepatocellular carcinoma (HCC) have not been fully elucidated. Our previous experiments of this proposal found that CASC11 was significantly upregulated in HCC tissues and associated with poor prognosis, and CASC11 can promote the proliferation, migration and invasion of HCC cells. Through further analysis of RNA pull-down combined with protein mass spectra, MeRIP-seq, RNA-seq and RIP-seq, we found that CASC11 could bind to UBE2T mRNA, recruited RNA demethylase ALKBH5 to downregulate its m6A modification level, and promoted its mRNA stability in an YTHDF2-dependent manner. This project will systematically investigate the role and molecular mechanism of CASC11-mediated m6A modification of UBE2T mRNA in the progression of liver cancer at the molecular, cellular, animal and clinical level, so as to provide theoretical basis for the CASC11 as a target for diagnosis and treatment of HCC.

lncRNA在多种生物学过程中发挥重要作用，但lncRNA CASC11在肝癌发生发展中发挥的功能和分子机制尚未完全阐明。我们前期研究发现，CASC11在肝癌组织中表达上调，并与不良预后相关，CASC11能促进肝癌细胞增殖和迁移侵袭。我们进一步通过RNA pull-down联合蛋白质谱、MeRIP-seq、RNA-seq和RIP-seq等多种组学分析并验证发现：CASC11上调癌基因UBE2T表达，CASC11可与UBE2T mRNA结合，并招募RNA去甲基化酶ALKBH5下调UBE2T mRNA的m6A修饰水平，同时抑制了UBE2T mRNA与阅读蛋白YTHDF2的结合。本项目将从分子、细胞、动物及临床标本水平系统研究CASC11介导UBE2T mRNA m6A修饰在肝癌发生发展中的作用及分子机制，为以CASC11作为肝癌诊断和治疗靶点提供理论依据。

肝癌是常见的恶性肿瘤之一，其恶性程度高，预后差。先前的研究已报道lncRNA和m6A修饰与肿瘤的发生和发展密切相关。本研究发现lncRNA CASC11在肝癌组织中显著高表达，并与不良预后相关。CASC11作为一个癌基因，能促进肝癌的生长和转移能力。机制研究发现，CASC11能与UBE2T mRNA结合，招募m6A去甲基化酶ALKBH5，使UBE2T m6A水平降低，YTHDF2与其结合减少，最终抑制UBE2T mRNA的降解，表达上调。本研究揭示了CASC11通过m6A修饰调控下游UBE2T表达的分子机制，为以CASC11作为治疗肝癌和判断预后的新型靶点提供了理论依据。