YTHDF1和YTHDF2在肝细胞癌增殖与迁移中的作用研究

RESEARCH ON THE ROLES OF YTHDF1 AND YTHDF2 IN HEPATOCELLULAR CARCINOMA PROLIFERATION AND METASTASIS

任军

11849443

硕士

生物学

李妍

2020-06-05

2020-06-10

哈尔滨工业大学

深圳

肝癌在全球范围内的致死率与发病率都位居前列，是人类生命健康的巨大威胁。而目前针对肝癌患者的诊治手段有限，肝癌患者的五年生存率极低。因此，揭示肝癌的发生发展中的分子机制显得尤为重要。近年来，随着对RNA修饰的不断研究，m6A在癌症中的重要性日益突显，为癌症发生发展的分子机制提供了新的思路。而m6A在肝癌中的作用还未得到完全阐明。基于以上原因，本文从TCGA和GEO数据库中获得了4个包含肝细胞癌样本高通量测序或芯片数据的数据集。选取m6A关键调节基因METTL3、METTL14、WTAP、FTO、ALKBH5、YTHDF1和YTHDF2，分析它们在肝细胞癌中的表达变化趋势。结果显示，肝癌组织中YTHDF1和YTHDF2的表达量显著高于癌旁组织。生存分析显示，YTHDF1、YTHDF2高表达患者具有更差的总生存时间（p < 0.001，p < 0.001）和无病生存时间（p = 0.0116，p = 0.002）。另外，结合患者临床数据，本文发现YTHDF1、YTHDF2的高表达与肝癌进展相关。基因集富集分析提示，YTHDF1与肝癌细胞DNA复制、细胞外基质互作有关；YTHDF2与肝癌细胞周期、细胞外基质互作有关。肝癌样本ChIP-seq数据显示，组蛋白H3K4me3可能调控了YTHDF1的表达。通过在肝癌细胞系中敲低或过表达YTHDF1/YTHDF2，本文发现YTHDF1与肝癌细胞的增殖无关，而YTHDF2的低表达会显著抑制肝癌细胞的增殖。此外，YTHDF1的低表达会促进肝癌细胞迁移，而YTHDF2的敲低会抑制肝癌细胞迁移。

As a kind of malignant tumor with high mortality and morbidity, liver cancer seriously threatens the health of humans. Today, the methods of diagnosis and treatment for liver cancer patients are poor, and the 5-year survival rate of liver cancer patients is very bad. Therefore, it is very important to reveal the pathogenesis of liver cancer. In recent years, with the continuous research on RNA modifications, the importance of m6A in cancer has become increasingly prominent. And m6A provides some new ideas for the molecular mechanism of cancer development. However, the role of m6A in hepatocellular carcinoma (HCC) has not been fully elucidated.For the above reasons, four datasets containing high-throughput sequencing or gene chip data of HCC samples from TCGA and GEO databases were analyzed in this paper. The key m6A regulators METTL3, METTL14, WTAP, FTO, ALKBH5, YTHDF1 and YTHDF2 were selected to analyze their expression pattern in HCC. The results showed that the expression of YTHDF1 and YTHDF2 in HCC tissues were significantly higher than that in para-cancer tissues. Survival analysis showed that patients with high YTHDF1 and YTHDF2 expression had worse overall survival (p < 0.001 and p < 0.001, respectively) and disease-free survival (p= 0.0116 and p=0.002, respectively). In addition, combined with the clinical data of HCC patients, it was found that the high expression of YTHDF1 and YTHDF2 was associated with the progression of HCC. Gene set enrichment analysis suggested that YTHDF1 was associated with DNA replication and extracellular matrix interaction in HCC cells. And YTHDF2 was related to HCC cell cycle and extracellular matrix interaction. ChIP-seq data showed that histone H3K4me3 may regulate the expression of YTHDF1 in HCC tissues.Furthermore, YTHDF1 doesn’t regulate the proliferation of HCC cells, while the low expression of YTHDF2 significantly inhibited the proliferation of HCC cells. In addition, knock down of YTHDF1 can improve HCC cells’ metastasis ability, while YTHDF2 knocked down inhibited the metastasis of HCC cells significantly.

肝细胞癌 m6A YTHDF1 YTHDF2 增殖 转移

hepatocellular carcinoma m6A YTHDF1 YTHDF2 proliferation metastasis

中文

联合培养

南方科技大学

任军. YTHDF1和YTHDF2在肝细胞癌增殖与迁移中的作用研究[D]. 深圳. 哈尔滨工业大学,2020.