Reduced Expression of METTL3 Promotes Metastasis of Triple-Negative Breast Cancer by m6A Methylation-Mediated COL3A1 Up-Regulation
Reduced Expression of METTL3 Promotes Metastasis of Triple-Negative Breast Cancer by m6A Methylation-Mediated COL3A1 Up-Regulation
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METTL3表达减少通过m6A甲基化介导的COL3A1上调促进三阴性乳腺癌转移
DOI：
10.3389/fonc.2020.01126
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发表时间：
2020-07-14
影响因子：
4.7
通讯作者：
Teng, Yuee
中科院分区：
文献类型：
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作者：
Shi, Yu;Zheng, Chunlei;Teng, Yuee
m6A调节剂引起的m6A修饰异常是多种肿瘤的共同特征；然而，对于哪种 m6A 调节剂在三阴性乳腺癌 (TNBC) 中发挥最重要的作用，人们知之甚少。本研究利用多个在线数据库分析m6A调节剂（METTL3、METTL14、WTAP、FTO和ALKBH5）对乳腺癌尤其是TNBC预后的影响时发现，甲基转移酶样3（METTL3）在乳腺癌中低表达，并且与TNBC中的短距离无转移生存密切相关。进一步的研究表明，敲除METTL3可以通过降低TNBC细胞系中m6A的水平来增强迁移、侵袭和粘附的能力。经鉴定并验证III型胶原α1链(COL3A1)为METTL3的靶基因。METTL3可通过增加其m6A甲基化下调COL3A1的表达，最终抑制TNBC细胞的转移。最后通过对乳腺癌组织进行免疫组化染色，证明TNBC中METTL3的表达与COL3A1呈负相关，而非TNBC中则不相关。这项研究证明了 m6A 修饰在转移中的潜在机制，并为 TNBC 的治疗提供了潜在的靶点。
The abnormal m6A modification caused by m6A modulators is a common feature of various tumors; however, little is known about which m6A modulator plays the most important role in triple-negative breast cancer (TNBC). In this study, when analyzing the influence of m6A modulators (METTL3, METTL14, WTAP, FTO, andALKBH5) on the prognosis of breast cancer, especially in TNBC using several on-line databases, methyltransferase-like 3 (METTL3) was found to have low expression in breast cancer, and was closely associated with short-distance-metastasis-free survival in TNBC. Further investigation showed that knockdown ofMETTL3could enhance the ability of migration, invasion, and adhesion by decreasing m6A level in TNBC cell lines. Collagen type III alpha 1 chain (COL3A1) was identified and verified as a target gene ofMETTL3.METTL3could down-regulate the expression ofCOL3A1by increasing its m6A methylation, ultimately inhibiting the metastasis of TNBC cells. Finally, with immunohistochemistry staining in breast cancer tissues, it was proved thatMETTL3expression was negatively correlated withCOL3A1in TNBC, but not in non-TNBC. This study demonstrated the potential mechanism of m6A modification in metastasis and provided potential targets for treatment in TNBC.