直肠癌发生过程中NSun2介导的mRNA甲基化对ATX的调控

项目名称： 直肠癌发生过程中NSun2介导的mRNA甲基化对ATX的调控

项目编号： No.31500619

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 张笑天

作者单位： 北京师范大学

项目金额： 21万元

中文摘要： ATX在高迁移率的肿瘤中高表达，与肿瘤发生及转移密切相关，但ATX在肿瘤细胞中的表达调控机制远未得到阐释。mRNA甲基化是基因转录后调控的新领域，RNA甲基转移酶NSun2在众多恶性肿瘤组织中高表达，但NSun2是否通过甲基化肿瘤相关基因调控其表达有待探讨。申请者前期研究发现：NSun2能够结合ATX mRNA 3’UTR并催化其发生m5C甲基化；在Colo320细胞中过表达NSun2可显著上调ATX表达，沉默NSun2则下调ATX表达。上述结果提示NSun2介导的mRNA甲基化可能参与直肠癌发生发展过程中ATX的表达调控。在此基础上，本项目拟进一步探讨NSun2介导的mRNA甲基化调控ATX表达的机制，利用NSun2-/-大鼠在动物整体水平研究NSun2-ATX通路在直肠癌发生与发展中的作用，从RNA表观修饰角度阐释肿瘤细胞中ATX的表达调控机制及其生物学意义。

中文关键词： 酶；RNA；相互作用；调控机制

英文摘要： Autotxin (ATX) is closely related to tumorigenesis and metastasis. However, the mechanism controlling ATX expression in human cancer is largely unknown.The expression of RNA methyltransferase NSun2 in numerous species of human cancers is greatly increased. However, whether NSun2 regulates tumor-related genes by methylating mRNAs of these genes has not been reported. In previous study, we have found that NSun2 could bind the 3’UTR of ATX mRNA, thereby methylating the ATX 3’UTR. Overexpression of NSun2 in Colo320 cells increased the expression of ATX, while the expression of ATX decreased in cells silenced with NSun2. These results indicate that NSun2 may regulate the expression of ATX through methylating ATX 3’UTR, this regulatory process may impact on the tumorigenesis and metastasis of rectal cancer. Based on these findings, we will set out to further investigate the mechanisms underlying the regulation of ATX by NSun2-mediated mRNA methylation. We will also investigate the impact of NSun2-ATX regulatory process on the tumorigenesis and metastasis of rectal cancer. Our study will not only elucidate the mechanisms controlling the expression of ATX in the tumorigenesis and metastasis of rectal cancer, but also provide evidence for the gene regulation studies of cancer as well as for the prevention and treatment of human cancers.

英文关键词： NSun2;Autotaxin;mRNA Methylation;Post-transcriptional Regulation