METTL7B通过m6A甲基化非编码RNA NEAT1促进非小细胞肺癌发生发展的机制研究

RNA m6A methylation is an important post-transcriptional modification, which is closely related to the development of various tumors,however, the underlying regulatory mechanism remains to be further explored. Recently, Methyltransferase-like proteins (METTL) are found to be a family of proteins that regulate a variety of cellular functions. Our previous study found that the expression of METTL7B in non-small cell lung cancer (NSCLC) was significantly increased and negatively correlated with prognosis. Overexpression of METTL7B accelerated the growth of lung cancer cells along with up-regulated the overall RNA m6A level. Transcriptome sequencing screening and cell experiments confirmed that METTL7B significantly up-regulated the important oncogene - long non-coding RNA NEAT1.We speculate that METTL7B may promote the growth of lung cancer cells by increasing NEAT1 by m6A methylation regulation.This project intends to further verify the effect of METTL7B-NEAT1 regulatory axis on the proliferation phenotype of NSCLC in vivo and in vitro.The detailed molecular mechanism of METTL7B in regulating the methylation of NEAT1 m6A was also explored by using Me-RIP, CLIP and gene editing technologies .This project will provide theoretical basis for elucidating the role of non-coding RNA epigenetic regulatory mechanism mediated by METTL7B in the development of NSCLC.

RNA m6A甲基化是重要的转录后修饰方式，与多种肿瘤发展密切相关，但其调控机制有待深入探索。甲基化转移酶样蛋白（METTL）是最近发现的甲基化修饰基因家族，调控多种细胞功能。我们前期研究发现该家族成员METTL7B在非小细胞肺癌（NSCLC）中表达显著升高且与预后负相关；过表达METTL7B加速肺癌细胞生长并上调其整体RNA m6A水平；转录组测序筛选并经细胞实验证实METTL7B可显著上调重要促癌基因-长链非编码RNA NEAT1。我们推测：METTL7B可能通过m6A甲基化修饰上调NEAT1从而促进肺癌细胞生长。我们拟通过体内外实验验证METTL7B-NEAT1调控轴对NSCLC生长的影响，利用Me-RIP、CLIP、基因编辑等技术剖析METTL7B调控NEAT1 m6A甲基化的详细分子机制和过程，为揭示其介导的非编码RNA表观遗传调控机制在NSCLC发生发展中的作用提供理论基础。

甲基化转移酶样蛋白（METTL）是最近发现的重要甲基化修饰基因家族，参与各种生物学调控过程。RNA m6A甲基化是广泛且重要的转录后修饰方式，与非小细胞肺癌（NSCLC）发生发展密切相关，但其调控机制仍需深入探究。我们前期研究发现该家族成员METTL7B在NSCLC中表达显著升高且与预后呈负相关；过表达METTL7B加速NSCLC细胞生长并上调其整体RNA m6A水平。本项目以METTL7B在NSCLC中的作用机制作为切入点，深入探究m6A RNA甲基化调控网络在NSCLC中的作用，阐明METTL7B通过m6A RNA甲基化修饰下游分子的详细分子机制。我们通过多种方法证明METTL7B是一个新的m6A甲基化转移酶，能结合大量mRNA及非编码RNA并调控RNA 的m6A甲基化修饰。METTL7B可通过m6A甲基化调控非编码RNA NEAT1的稳定性促进NSCLC的发生发展。另外，METTL7B可调控RNA的5'UTR的甲基化，METTL7B能与多个翻译起始蛋白在RNA的5’UTR区域聚集，并共同调控肿瘤增殖相关的下游基因的转录、翻译等过程。本项目为揭示METTL7B介导RNA表观遗传调控机制在NSCLC发生发展中的作用提供理论基础。

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