DNA甲基化、组蛋白修饰调控非小细胞肺癌lncRNA MALAT1表达的分子机制研究

Lung cancer is a serious disease harming human health.However,the mechanisms have not yet been elucidated. At present long non-coding RNA（lncRNA）has become a research focus. Research of lncRNA in tumor field mainly concentrated in the effect of expression level of MALAT1 on the tumorigenesis and development, but study regulating lncRNA expression is less. Study that lncRNA in tumor is regulated by epigenetic forms has been not yet carried out at home and abroad. MALAT1 is the first functional lncRNA that is identified in lung cancer. MALAT1 promotes the migration and metastasis of non-small cell lung cancer (NSCLC). Our previous results showed that DNA methylation and histone modification,which existed in upstream regulatory region of MALAT1 gene,is closely related to the expression of MALAT1. In combination with domestic and foreign research, we propose that Dnmt1,MeCP2,PRC2 and MLL anticipate the DNA methylation and histone modification which induce the binding model of MeCP2,YB-1 and TDP-43 to alter and then regulate the expression of MALAT1.Therefore, this project will confirm these assumptions and provide new ideas and targets for NSCLC treatment with DNA methylation and histone modifications as the starting point and with NSCLC as the object of research based on epigenetic research ideas.

肺癌作为危害人类健康的重大疾病，机制尚未阐明。目前，lncRNA成为研究热点。lncRNA在肿瘤领域的研究主要集中在其表达水平对肿瘤发生发展的影响，而有关调控lncRNA表达机制的研究较少，肿瘤中lncRNA受表观遗传形式调控方面的研究在国内外尚未开展。MALAT1是第一个在肺癌中鉴定的功能性lncRNA，MALAT1促进非小细胞肺癌侵袭转移，课题组前期发现，MALAT1基因上游调控区存在DNA甲基化、组蛋白修饰和非小细胞肺癌MALAT1基因表达密切相关，结合国内外有关研究，提出Dnmt1、MeCP2、PRC2、MLL参与DNA甲基化和组蛋白修饰，导致MeCP2、YB-1、TDP-43结合状态改变，从而调控MALAT1基因表达的设想。因此，本课题拟以DNA甲基化和组蛋白修饰为切入点，基于表观遗传学的研究思路，以非小细胞肺癌为研究对象，证实上述设想，为非小细胞肺癌的治疗提供新思路、新靶点。

肺癌作为危害人类健康的重大疾病，机制尚未阐明。目前，lncRNA成为研究热点。lncRNA在肿瘤领域的研究主要集中在其表达水平对肿瘤发生发展的影响，而有关调控lncRNA表达机制的研究较少，肿瘤中lncRNA受表观遗传形式调控方面的研究在国内外更少。MALAT1是第一个在肺癌中鉴定的功能性lncRNA。本研究采用Real time PCR、甲基化特异性PCR、免疫沉淀、染色质免疫沉淀分析、荧光素酶报告基因分析等方法，以非小细胞肺癌为研究对象，阐述了：（1）MALAT1在非小细胞肺癌进展尤其是侵袭转移中发挥着重要作用；（2）DNA甲基化调控了MALAT1表达；（3）组蛋白修饰调控MALAT1表达；（4）转录因子TDP-43参与调控MALAT1的表达。上述结果表明DNA甲基化和组蛋白修饰调控MALAT1表达进而影响其功能。研究成果将具有重要理论意义和潜在的应用前景，可以为临床治疗提供良好的前期基础。