BACKGROUND Emerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to cervical cancer (CC) tumorigenesis and development. Previous work showed that miR-484 which regulated the EMT process was obviously downregulated in CC. However, little is known about the precise mechanism. RESULTS We found that the deficiency of EZH2-recruited DNA methyltransferases DNMT1 reduced the CpG methylation of miR-484 promoter and then increased the miR-484 expression. Furthermore, the cell membrane-bound matrix metalloproteinase (MMP14) and the hepatocyte nuclear factor 1A (HNF1A) were found to be downregulated by miR-484. miR-484 repressed the expression of MMP14 and HNF1A inhibiting CC growth and metastasis in vitro and in vivo. Upregulation of MMP14 and HNF1A promotes the CC cell adhesion and EMT, all of which contribute to cell motility and metastasis. Moreover, miR-484 negatively regulates the WNT/MAPK and TNF signaling pathway by downregulating HNF1A and MMP14 respectively. Thus, miR-484, who is downregulated by DNMT1-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting MMP14 and HNF1A expression in CC. CONCLUSION Our finding characterizes miR-484 as a key suppressive regulator in CC metastasis and reveals a DNMT1-mediated epigenetic mechanism for miR-484 silencing, expanding our understanding of the molecular mechanism underlying CC progression and metastasis.

中文翻译：

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通过EZH2介导的miR-484沉默而募集的DNMT1通过MMP14和HNF1A促进宫颈癌细胞的恶性肿瘤。

背景技术越来越多的证据表明，microRNA（miRNA）的失调有助于宫颈癌（CC）的发生和发展。先前的工作表明，调节EMT过程的miR-484在CC中明显下调。但是，对精确的机制知之甚少。结果我们发现缺乏EZH2的DNA甲基转移酶DNMT1降低了miR-484启动子的CpG甲基化，然后增加了miR-484的表达。此外，发现细胞膜结合基质金属蛋白酶（MMP14）和肝细胞核因子1A（HNF1A）被miR-484下调。miR-484在体内外均抑制MMP14和HNF1A的表达，抑制CC的生长和转移。MMP14和HNF1A的上调促进CC细胞粘附和EMT，所有这些都有助于细胞运动和转移。而且，miR-484分别通过下调HNF1A和MMP14负调控WNT / MAPK和TNF信号通路。因此，miR-484在启动子中被DNMT1介导的高甲基化下调，通过抑制CC中MMP14和HNF1A的表达而发挥其抑癌作用。结论我们的发现将miR-484作为CC转移的关键抑制调节因子，并揭示了DNMT1介导的miR-484沉默表观遗传机制，从而扩展了我们对CC转移和转移的分子机制的了解。通过抑制CC中MMP14和HNF1A的表达而发挥抑癌作用。结论我们的发现将miR-484作为CC转移的关键抑制调节因子，并揭示了DNMT1介导的miR-484沉默表观遗传机制，从而扩展了我们对CC转移和转移的分子机制的了解。通过抑制CC中MMP14和HNF1A的表达来发挥肿瘤抑制作用。结论我们的发现将miR-484表征为CC转移的关键抑制调节因子，并揭示了DNMT1介导的miR-484沉默的表观遗传机制，从而扩大了我们对CC进展和转移的分子机制的了解。