MECP2 promotes the migration and invasion of gastric cancer cells by modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription.
MECP2 promotes the migration and invasion of gastric cancer cells by modulating the Notch1/c-Myc/mTOR signaling pathways by suppressing FBXW7 transcription.
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DOI：
10.21203/rs.3.rs-48700/v1
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发表时间：
2020-07
影响因子：
5.3
通讯作者：
Lingyu Zhao;Xiaofei Wang;Juan Yang;Q. Jiang;Jing Zhang;Yannan Qin;Lumin Wang;Liying Liu;L. Ni
中科院分区：
文献类型：
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作者：
Lingyu Zhao;Xiaofei Wang;Juan Yang;Q. Jiang;Jing Zhang;Yannan Qin;Lumin Wang;Liying Liu;L. Ni
甲基化CpG结合蛋白2（MECP 2）是一种表观遗传调节因子，促进许多癌症的发生和进展。然而，其在胃癌（GC）迁移和侵袭中的作用以及潜在的分子机制仍不清楚。在本研究中，我们发现MECP 2促进了胃癌细胞的迁移、侵袭和转移。分子机制的研究表明，MECP 2通过与FBXW 7启动子区域的甲基化CpG位点结合，抑制了GC中F-box和WD 40结构域蛋白7（FBXW 7）的转录。胃癌组织中MECP 2表达与FBXW 7水平呈显著负相关。FBXW 7在胃癌组织和细胞系中表达显著下调，FBXW 7低表达与不良的临床病理特征相关。FBXW 7通过调节Notch 1/c-Myc/mTOR信号通路抑制细胞迁移和侵袭，并且FBXW 7的敲低逆转了沉默MECP 2的作用。此外，MECP 2通过在转录水平上抑制FBXW 7表达上调Notch 1/c-Myc/mTOR信号通路。该研究表明，MECP 2通过抑制FBXW 7转录来调节Notch 1/c-Myc/mTOR信号通路，从而促进GC细胞的迁移和侵袭。提示MECP 2可能成为胃癌治疗的新靶点。
Methyl-CpG-binding protein 2 (MECP2), an epigenetic regulatory factor, promotes the carcinogenesis and progression of a number of cancers. However, its role in the migration and invasion of gastric cancer (GC), as well as the underlying molecular mechanisms, remain unclear. In this study, we found that MECP2 promoted the migration, invasion and metastasis of GC cells. Investigation of the molecular mechanism revealed that MECP2 repressed F-box and WD40 domain protein 7 (FBXW7) transcription in GC by binding to the methylated CpG sites in the FBXW7 promoter region. MECP2 expression was markedly negatively correlated with the FBXW7 level in GC tissues. FBXW7 expression was significantly downregulated in GC tissues and cell lines, and low FBXW7 expression was correlated with unfavorable clinicopathologic features. FBXW7 inhibited cell migration and invasion by regulating the Notch1/c-Myc/mTOR signaling pathways, and knockdown of FBXW7 reversed the effects of silencing MECP2. Moreover, MECP2 upregulated the Notch1/c-Myc/mTOR signaling pathways by inhibiting FBXW7 expression at the transcriptional level. This study demonstrates that MECP2 promotes the migration and invasion of GC cells by modulating the Notch1/c-Myc/mTOR signaling pathways via suppression of FBXW7 transcription. These findings suggest that MECP2 may be a novel effective therapeutic target in GC.