RNA甲基化转移酶NSun2对乳腺癌发生发展的调控机制研究

The tRNA methltransferase NSun2 has been described as a positive regulator for cell cycle progression,while the mechanisms underlying remain unkown.In this study,we have examined the role of NSun2-mediated mRNA methylation in the regulation of CDK1 translation.Knockdown of NSun2 reduced the protein level of CDK1,while overexpression of NSun2 exhibited oppsite effect.Neither overexpression nor knockdown of NSun2 could alter the mRNA level of CDK1,suggesting that NSun2 may regulate the expression of CDK1 at translation level.Further study showed that NSun2 interacted with the CDK1 3'UTR and methylated it at A1244 and A1268.NSun2-mediated mRNA metyhlation is the basement that it promoted CDK1 translation.Both NSun2 and CDK1 reduced in G1 phase,but increased in S and G2/M phases.More importantly,cells silenced NSun2 exibited G2/M arrest and slow proliferation.The cell cycel change is an important cause leading to the generation and development of a tumour . We will intensively study how the mechanism that NSun2 promotes CDK1 translation by methylating the CDK1 3'UTR influence the genetation ,development and metastasis of breast cancer ,and the results may supply a new judgement for its early diagnosis and treatment evaluation.

NSun2是以一主要定位于核仁的RNA甲基转移酶，可参与细胞周期，细胞生长，细胞凋亡，肿瘤发生与发展方面的调控，但是机制都不明确。我们对NSun2调控细胞生长的分子机制做了深入探讨，结果发现：1）NSun2可以影响CDK1蛋白水平，而不影响其mRNA水平，提示NSun2对CDK1的调控发生在翻译水平；2）NSun2与CDK1 3'UTR直接结合并催化A1244和A1268甲基化；3）NSun2介导的甲基化是其促进CDK1翻译的基础；4）CDK1与NSun2在细胞周期波动上有一致性。CDK1不但与cyclinB一起促进细胞周期的G2-M期转变，也能促进细胞从G1期进入S期。肿瘤的发生发展中，细胞周期的改变时很重要的一个因素。本课题拟以NSun2通过甲基化CDK1 3'UTR而促进其翻译这一分子机制对乳腺癌的发生，发展和转移等的影响等进行深入探索，从而为乳腺癌的早期诊断和预防评估提供新的依据

NSUN2是一种RNA甲基化转移酶，与肿瘤的发展密切相关，但是NSUN2在乳腺癌中表达的功能和机制以及其与乳腺癌的临床特征相关性还未有研究。为研究NSUN2在乳腺癌中表达的变化和功能，本研究使用乳腺癌细胞和根据AJCC标准界定不同分期的乳腺癌组织检测NSUN2表达的改变，使用乳腺癌细胞检测功能的改变。NSUN2过表达后可以促进细胞增殖，迁移和浸润，NSUN2敲出后抑制体内外细胞的增殖，迁移和浸润。NSUN2表达水平与其启动子的甲基化有关。我们的研究结果显示NSUN2与临床分期，肿瘤分类，病理分化级别相关，同时也与ER、PR和Ki-67水平相关。我们的研究为NSUN2在乳腺癌细胞中表达的机制提供新的思路，为进一步研究乳腺癌的治疗靶标，比如NSUN2，提供基础和铺垫。