tRNA甲基化酶ALKBH8调节翻译促结直肠癌发生的机制研究

WNT/β-catenin信号通路是驱动结直肠癌发生的关键信号。翻译层面调节基因表达对于WNT驱动的结直肠癌发生至关重要，然而对该过程认识有限。我们预实验结果显示，tRNA（U34）甲基化酶ALKBH8在结直肠癌组织中高表达且受β-catenin调控，可能通过调节肠道干细胞活性发挥促癌作用；核糖体展示结果提示，ALKBH8主要影响一批癌基因的翻译延伸。基于此，本项目将利用肠道干细胞条件性敲除鼠深入研究ALKBH8对肠道干性和肿瘤发生的调节作用，阐明其调控翻译的靶mRNA及分子机制，并在临床标本中探索ALKBH8在结直肠癌发病中的意义。本项目将明确ALKBH8在翻译层面对基因表达进行重编程以介导WNT驱动的肠癌发生，丰富我们对tRNA修饰生物学功能的认识，拓宽结直肠癌发病机制研究思路。

WNT/β-catenin signaling drives the tumorigenesis of colorectal cancer. Regulation of gene expression at the translational level is essential for WNT-driven tumorigenesis, which remains to be studied. Previous studies in our lab revealed that ALKBH8, a tRNA (U34) methyltransferase, is highly expressed in colorectal cancer tissue and regulated by β-catenin. Our data also suggested that ALKBH8 promotes colorectal tumorigenesis by regulating the stemness of intestinal stem cells. Ribosome profiling data revealed that ALKBH8 mainly regulates the translational elongation of a subset of oncogenes. These preliminary results led to the central hypothesis that ALKBH8 reprograms gene expression at the translational level to mediate WNT-driven tumorigenesis. To test this hypothesis, three aims are proposed: 1) Define the role of ALKBH8 in regulating intestinal stemness and tumorigenesis by using intestinal stem cell conditional knockout mice; 2) Explore the molecular mechanism of ALKBH8-regulated mRNA translation; and 3) Evaluate the clinical relevance of ALKBH8 expression in colorectal cancer development. This project will not only expand our understanding of the biological function of tRNA modifications but also open up new avenues of research on the pathogenesis of colorectal cancer.