m6A识别蛋白YTHDF1介导的EIF3翻译起始复合物的组装在卵巢癌中的作用及机制研究

Ovarian cancer is the most lethal gynecologic malignancy in women and the pathogenesis of this disease remains unclear. m6A (N6-methyladenosine）is one of RNA methylation modes，which is involved in biological progress and pathogenesis through regulating RNA alternative splicing, stability and translation. We found the m6A reader YTHDF1 acts as an oncogene in ovarian cancer cells through regulating growth and metastasis of ovarian cancer cells in vitro and in vivo. By multiple-omics analysis, we identified the subunit of translation initiation factor EIF3, EIF3C, as the target gene of YTHDF1. Polysome profiling demonstrated that YTHDF1 regulated EIF3C expression through affecting EIF3C translation. Further studies would be performed to dissect the precise mechanism of YTHDF1 in the pathogenesis of ovarian cancer. Meanwhile, the correlation of expression between YTHDF1 and EIF3C in ovarian cancer samples would be explored and the rescue assay of EIF3C on YTHDF1 in vitro and in vivo would be performed to reveal the role and mechanism of YTHDF1 in ovarian cancer. It is possible to further understand the pathogenesis of high grade serous carcinoma in ovary and to provide new diagnostic and therapeutic targets for ovarian cancer.

卵巢癌是妇科恶性肿瘤中致死率最高的肿瘤，发病机制仍未阐明。N6-甲基腺嘌呤（N6-methyladenosine，m6A）是较为常见的一种RNA甲基化修饰方式。m6A修饰可以通过调控基因剪接、RNA稳定性和mRNA翻译等方面在生理和病理过程中发挥重要的作用。本项目前期研究发现m6A识别蛋白YTHDF1在卵巢癌细胞中作为一个癌基因参与细胞生长及转移。通过多重组学联合分析鉴定发现翻译起始因子EIF3中的核心亚基EIF3C为YTHDF1的靶基因，核糖体图谱实验发现YTHDF1通过影响EIF3C的翻译而调控其表达。本项目将深入阐明YTHDF1对翻译起始因子EIF3C的调控机理，并通过在组织标本水平相关性表达分析以及在细胞和体内水平功能挽救实验，以进一步了解YTHDF1在浆液性卵巢癌中的作用及机制，将可能为卵巢癌诊断及治疗提供新靶点。

卵巢癌在妇科恶性肿瘤中死亡率最高，近70%的卵巢癌病人就诊时为晚期。晚期患者五年总生存率低于30%。卵巢癌发病机制不明仍是造成卵巢癌致死率高的关键因素。m6A甲基化是真核生物中最为普遍的一种RNA修饰，通过调控RNA的剪接、降解、转运及翻译影响RNA代谢的各个方面。m6A修饰的失调参与多种恶性肿瘤的起始和进展，其中包括干细胞癌、肺癌及急性髓性白血病等。在不同肿瘤中，m6A调控通路促进或抑制肿瘤的发生与发展。本项目研究了m6A阅读器蛋白YTHDF1在浆液性卵巢癌中的作用及分子机制。发现YTHDF1在卵巢癌中高度扩增，其表达显著上调，并且与卵巢癌患者的不良预后相关。体内外功能实验显示，YTHDF1能促进卵巢癌的生长及转移。通过联合多组学分析策略，我们鉴定到YTHDF1的关键靶基因为翻译起始因子EIF3C。YTHDF1以m6A依赖的方式调控EIF3C的翻译，并促进卵巢癌细胞中整体蛋白的翻译。同时，EIF3C与YTHDF1在卵巢癌中的蛋白表达呈显著正相关。YTHDF1-EIF3C调控轴在卵巢癌的恶性进展中发挥着重要作用。YTHDF1作为卵巢癌中的潜在治疗靶点，具有一定的转化和应用前景。