PDLIM5通过下调EIF2B4 m6A修饰抑制肝癌发生的分子机制研究

肝癌是危害人类健康的重大疾病之一，其分子机制仍有待进一步阐明。细胞癌变过程伴随大量基因的异常表达，真核翻译起始因子（eIFs）在其中发挥关键作用。在前期研究中，我们发现细胞骨架蛋白PDLIM5在肝癌中低表达，且与EIF2B4的表达呈负相关，提示PDLIM5是一个潜在的抑癌基因。此外，过表达PDLIM5可通过抑制EIF2B4从而诱导细胞周期阻滞，抑制肝癌细胞的增殖。进一步研究发现，PDLIM5可抑制EIF2B4 mRNA的m6A修饰，从而促进EIF2B4 mRNA的降解，导致EIF2B4蛋白表达下调，提示PDLIM5可能通过该途径发挥抑癌基因的功能。在此基础上，拟利用体内模型进一步明确PDLIM5在肝癌发生中的作用，阐明PDLIM5通过下调EIF2B4 m6A修饰抑制肝癌细胞生长的机制，明确PDLIM5的病理学意义及其潜在应用价值，为肝癌的临床治疗提供理论依据。

Hepatocellular carcinoma (HCC) remains a major challenge of human health, while underlying mechanisms have been poorly understood. The aberrant expression of massive genes is one of hallmarks of cancer, where the regulation of eIFs plays a key role. In our previous study, we found that the cytoskeleton gene PDLIM5 is downregulated in HCC and negatively correlated with EIF2B4, suggesting PDLIM5 as a potential tumor suppressor in HCC. Besides, overexpression of PDLIM5 represses the expression of EIF2B4, leading to the cell cycle arrest of HCC cells. In addition, PDLIM5 inhibits m6A modification of EIF2B4 mRNA, which promotes the RNA degradation. These observations indicate that PDLIM5 inhibits HCC growth through m6A modification of EIF2B4. Therefore, we will further validate the function of PDLIM5 in HCC by animal models, elucidating the mechanisms underlying PDLIM5-mediated downregulation of m6A modification on EIF2B4, and confirm the pathological significance of PDLIM5 in HCC. This project will provide molecular basis for the clinic management of HCC.