The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1
The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1
复制标题
m6A甲基转移酶METTL3通过调节LEF1的m6A水平促进骨肉瘤进展
DOI：
10.1016/j.bbrc.2019.06.128
复制
发表时间：
2019-08-27
影响因子：
3.1
通讯作者：
Song, Dianwen
中科院分区：
文献类型：
--
作者：
Miao, Wujun;Chen, Jiajia;Song, Dianwen
骨肉瘤（OS）是最常见和最具侵袭性的恶性骨肉瘤，好发于儿童和青少年快速生长的骨骼。然而，OS发展的潜在分子机制尚未完全阐明。N6-甲基腺苷（m6 A）是最常见的mRNA内部化学修饰，其参与癌症发展中的许多病理过程。然而，其在OS中的作用和调节机制尚不清楚。本研究旨在探讨m6 A及其甲基转移酶L3在OS发生中的作用。结果显示，人骨肉瘤组织和骨肉瘤细胞系中mRNA甲基化水平和胃L3表达水平均上调。慢病毒介导的胃L3基因沉默可抑制HOS和SAOS-2细胞的增殖、迁移和侵袭能力。进一步的机制分析表明，胃L3沉默降低了m6 A甲基化水平和淋巴增强子结合因子1（LEF 1）总mRNA水平，进而抑制了Wnt/6-catenin信号通路的活性。此外，LEF 1过表达消除了胃L3沉默对OS细胞增殖、迁移和侵袭能力的抑制作用。总之，这些结果表明，m6 A甲基转移酶L3通过调节LEF 1的m6 A水平和激活Wnt/β-catenin信号通路促进骨肉瘤细胞的进展。(C)2019爱思唯尔公司All rights reserved.
Osteosarcoma(OS) is the most common and aggressive malignant bone sarcoma,which occurs in rapidly growing bones in children and adolescents. However, the underlying molecular mechanisms of OS development have not been fully illustrated. N6-Methyladenosine (m6A) is the most prevalent internal chemical modification of mRNAs, which is involved in many pathological processes in cancer development. However, its role and regulatory mechanism in OS remain unknown. In this study, we aimed to investigate the roles of m6A and its methyltransferase METTL3 in OS development. The results showed that m6A level for RNA methylation and the expression level of METTL3 were up-regulated in human OS tissues and OS cell lines. Functionally, lentivirus-mediated METTL3 silence in HOS and SAOS-2 cells inhibited the cell proliferation, migration and invasion ability. Further mechanism analysis suggested that METTL3 silence decreased the m6A methylation and total mRNA level of lymphoid enhancer binding factor 1 (LEF1), followed by inhibited the activity of Wnt/6-catenin signaling pathway. Moreover, LEF1 over-expression abrogates the repressive effects of METTL3 silence on the proliferation, migration and invasion abilities of OS cells. Together, these results revealed that the m6A methyltransferase METTL3 promotes osteosarcoma cell progression by regulating the m6A level of LEF1 and activating Wnt/beta-catenin signaling pathway. (C) 2019 Elsevier Inc. All rights reserved.