miRNA-584-3p inhibits gastric cancer progression by repressing Yin Yang 1- facilitated MMP-14 expression.
miRNA-584-3p inhibits gastric cancer progression by repressing Yin Yang 1- facilitated MMP-14 expression.
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miRNA-584-3P通过抑制阳阳1-促进的MMP-14表达来抑制胃癌的进展。
DOI：
10.1038/s41598-017-09271-5
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发表时间：
2017-08-21
影响因子：
4.6
通讯作者：
Tong Q
中科院分区：
文献类型：
--
作者：
Zheng L;Chen Y;Ye L;Jiao W;Song H;Mei H;Li D;Yang F;Li H;Huang K;Tong Q
最近的证据表明启动子靶向的内源性microRNA（miRNAs）在调节基因转录中的新兴作用。然而，影响胃癌中基质金属蛋白酶14（MMP-14）转录的miRNAs仍然未知。在此，我们通过对公共数据集的综合挖掘，确定了阴阳1（YY 1）和miRNA-584- 3 p（miR-584- 3 p）在MMP-14启动子内的邻近靶向位点。我们证明YY 1直接靶向MMP-14启动子，以促进其在胃癌细胞中的表达。相反，miR-584- 3 p识别MMP-14启动子内的互补位点，从而抑制其表达。从机制上讲，miR-584- 3 p与Argonaute 2相互作用，招募zeste同源物2和常染色质组蛋白赖氨酸甲基转移酶2的增强子，导致抑制性表观遗传标记物的富集和YY 1与MMP-14启动子的结合减少。miR-584- 3 p通过抑制YY 1介导的MMP-14表达，抑制胃癌细胞体内外的成瘤性和侵袭性。在临床胃癌组织中，YY 1和miR-584- 3 p的表达与MMP-14水平呈正或负相关。此外，miR-584- 3 p和YY 1分别是与胃癌患者有利和不利预后相关的独立预后因素。这些数据表明，miR-584- 3 p直接靶向MMP-14启动子以抑制YY 1促进的MMP-14表达并抑制胃癌的进展。
Recent evidence shows the emerging roles of promoter-targeting endogenous microRNAs (miRNAs) in regulating gene transcription. However, miRNAs affecting the transcription of matrix metalloproteinase 14 (MMP-14) in gastric cancer remain unknown. Herein, through integrative mining of public datasets, we identified the adjacent targeting sites of Yin Yang 1 (YY1) and miRNA-584-3p (miR-584-3p) within MMP-14 promoter. We demonstrated that YY1 directly targeted the MMP-14 promoter to facilitate its expression in gastric cancer cells. In contrast, miR-584-3p recognized its complementary site within MMP-14 promoter to suppress its expression. Mechanistically, miR-584-3p interacted with Argonaute 2 to recruit enhancer of zeste homolog 2 and euchromatic histone lysine methyltransferase 2, resulting in enrichment of repressive epigenetic markers and decreased binding of YY1 to MMP-14 promoter. miR-584-3p inhibited the in vitro and in vivo tumorigenesis and aggressiveness of gastric cancer cells through repressing YY1-facilitated MMP-14 expression. In clinical gastric cancer tissues, the expression of YY1 and miR-584-3p was positively or negatively correlated with MMP-14 levels. In addition, miR-584-3p and YY1 were independent prognostic factors associated with favorable and unfavorable outcome of gastric cancer patients, respectively. These data demonstrate that miR-584-3p directly targets the MMP-14 promoter to repress YY1-facilitated MMP-14 expression and inhibits the progression of gastric cancer.
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作者：
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