The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells
The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells
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DOI：
10.3892/ijo.2017.4219
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发表时间：
2018-02-01
影响因子：
5.2
通讯作者：
Ogawa, Kazuhiko
中科院分区：
文献类型：
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作者：
Taketo, Kosuke;Konno, Masamitsu;Ogawa, Kazuhiko
N-6-甲基腺苷（m（6）A）是哺乳动物mRNA中最丰富的表位转录组修饰。近年来，m（6）A表观转录组学的研究取得了重大进展，表明其通过调节RNA稳定性、mRNA剪接、microRNA加工和mRNA翻译在肿瘤的发生和发展中发挥重要作用。然而，以甲基转移酶样3（methyltransferase-like 3，简称MTL 3）为代表的酶组分通过何种方式动态调节或书写m（6）A，以及m（6）A对众多基因中的每一个基因的重要性如何，仍不清楚。我们关注胰腺癌中的胃L3，尽管多学科治疗的发展，其预后仍不令人满意。我们用短发夹状RNA建立了胃L3基因敲低的胰腺癌细胞系。尽管形态和增殖变化不受影响，但去除胃L3的细胞对抗癌试剂如吉西他滨、5-氟尿嘧啶、顺铂和辐射表现出更高的敏感性。我们的数据表明，胃L3是增强胰腺癌患者治疗效果的有效靶点。此外，我们进行了cDNA表达分析，然后分别使用数据库注释，可视化和集成发现和搜索工具检索相互作用的基因/蛋白质数据库进行基因本体和蛋白质-蛋白质相互作用分析。结果表明，胃L3
N-6-methyladenosine (m(6)A) is the most abundant epitranscriptome modification in mammalian mRNA. Recent years have seen substantial progress in m(6)A epitranscriptomics, indicating its crucial roles in the initiation and progression of cancer through regulation of RNA stabilities, mRNA splicing, microRNA processing and mRNA translation. However, by what means m(6)A is dynamically regulated or written by enzymatic components represented by methyltransferase-like 3 (METTL3) and how m(6)A is significant for each of the numerous genes remain unclear. We focused on METTL3 in pancreatic cancer, the prognosis of which is not satisfactory despite the development of multidisciplinary therapies. We established METTL3-knockdown pancreatic cancer cell line using short hairpin RNA. Although morphologic and proliferative changes were unaffected, METTL3-depleted cells showed higher sensitivity to anticancer reagents such as gemcitabine, 5-fluorouracil, cisplatin and irradiation. Our data suggest that METTL3 is a potent target for enhancing therapeutic efficacy in patients with pancreatic cancer. In addition, we performed cDNA expression analysis followed by gene ontology and protein-protein interaction analysis using the Database for Annotation, Visualization, and Integrated Discovery and Search Tool for the Retrieval of Interacting Genes/Proteins databases, respectively. The results demonstrate that METTL3