RNA甲基化转移酶NSUN2对膀胱癌发生发展的调控机制研究

Bladder cancer (BC) is one of the commonly diagnosed cancers in the world and has the highest rate of recurrence of any malignancy. However, survival in malignant BC is still low, and the therapy of BC remains a challenge. Identifying new genes that promote or suppress BC development will benefit for cancer therapy. NSun2 (NOP2/Sun domain family, member 2) is a nucleolar RNA methyltransferase implicated in cell proliferation and human cancers; however, the molecular mechanism has not been elucidated. From whole-genome sequencing data of 99 patients with transitional cell carcinoma (TCC), we discovered that the genome locus of NSUN2 is amplified in most DNA-sequenced tumors. With our preliminary data, we firstly validated that NSUN2 is amplified in most case of TCC. And the overexpression of NSUN2 is associated with poor clinical outcome, suggesting a proto-oncogene role in BC. Knock-down of NSUN2 in T24 cells led to decreased cell proliferation, colony formation and tumor growth. From further study, we found that NSUN2 is involved in the methylation of HDAC2 mRNA. We assumed that the regulatory role of NSUN2 in BC is through the methylation of HDAC2 mRNA that could affect the expression of HDAC2 protein and then its biological function. Therefore, we plan: 1) Reveal the clinical significance of NSUN2 amplification and protein expression in more BC samples; 2) Using multiple cell lines and animal models to study its biological function; 3) Investigating the regulatory role of NSUN2 in the methylation of HDAC2 mRNA, protein expression and its biological function. Our study may provide a new therapeutic target and strategy in BC.

膀胱癌是泌尿系统最常见的恶性肿瘤之一，其发生、发展机制尚未清楚，也缺乏有效的治疗靶点。NSUN2作为重要的RNA甲基化转移酶，催化RNA 5-甲基胞嘧啶修饰，调控RNA稳定性、翻译能力。申请者前期对99个膀胱移行细胞癌组织进行了全基因组测序，并在组织样本中证实，NSUN2在许多膀胱癌肿瘤组织中发生基因扩增，蛋白高表达，与临床预后负相关。进一步结果表明: 在膀胱癌T24细胞系中，敲低NSUN2，其细胞的体外增殖、克隆形成和体内皮下成瘤能力等, 均受到明显抑制, 其作用机制可能是通过调控HDAC2 mRNA的甲基化水平。本项目拟收集更多的膀胱癌组织样本, 明确NSUN2的临床意义和价值；利用多种膀胱癌细胞系和实验动物模型, 验证NSUN2的生物学功能, 并阐明其机制是通过调控HDAC2 mRNA的甲基化水平，从而影响HDAC2蛋白的表达。本项目的完成, 可能为膀胱癌提供新的治疗靶点和策略。

膀胱癌是泌尿系统最常见的恶性肿瘤之一，其发生、发展机制尚未清楚，也缺乏有效的治疗靶点。5-甲基胞嘧啶是RNA常见的修饰，但在恶性肿瘤中的作用尚不清楚。我们分析了膀胱尿路上皮癌中的RNA5-甲基胞嘧啶修饰，发现了大量癌基因RNA高5-甲基胞嘧啶位点，并证明YBX1能识别5-甲基胞嘧啶修饰的mRNA，NSUN2和YBX1能诱导HDGF的3’非翻译区域5-甲基胞嘧啶修饰。临床样本中同时高表达NUSN2，YBX1和HDGF提示最差的预后。我们的研究揭示了一个新的癌基因作用机制，为膀胱癌提供新的治疗靶点和策略。