miR-125b targets DNMT3b and mediates p53 DNA methylation involving in the vascular smooth muscle cells proliferation induced by homocysteine
miR-125b targets DNMT3b and mediates p53 DNA methylation involving in the vascular smooth muscle cells proliferation induced by homocysteine
复制标题
DOI：
10.1016/j.yexcr.2016.07.007
复制
发表时间：
2016-09-10
影响因子：
3.7
通讯作者：
Jiang, YiDeng
中科院分区：
文献类型：
--
作者：
Cao, ChengJian;Zhang, HuiPing;Jiang, YiDeng
MicroRNAs(MiRNAs)是一种短小的非编码RNA，在细胞增殖、分化和凋亡等广泛的生物学过程中发挥着重要作用。我们前期的研究发现，同型半胱氨酸(Hcy)能刺激血管平滑肌细胞(VSMCs)增殖，但其作用机制尚未完全阐明。在此，我们发现同型半胱氨酸诱导的VSMCs增殖与在体外和ApoE基因敲除小鼠中miR-125b的表达降低、p53的高甲基化及其表达降低以及DNA(胞嘧啶-5)甲基转移酶3b(Dnmt3b)的上调相对应。并且，我们发现Dnmt3b是miR-125b的靶标，并通过双荧光素酶报告实验和Western blotting进行了验证。此外，对Dnmt3b的siRNA干扰显著降低了P53的甲基化水平，揭示了Dnmt3b在P53高甲基化中的作用。MIR-125b的转染进一步证实了其对P53基因甲基化状态和VSMCs增殖的调节作用。提示同型半胱氨酸诱导的VSMCs增殖可能存在miR-125b-Dnmt3b-P53信号通路。(C)2016 Elsevier Inc.保留所有权利。
MicroRNAs (miRNAs) are short non-coding RNA and play crucial roles in a wide array of biological processes, including cell proliferation, differentiation and apoptosis. Our previous studies found that homocysteine(Hcy) can stimulate the proliferation of vascular smooth muscle cells (VSMCs), however, the underlying mechanisms were not fully elucidated. Here, we found proliferation of VSMCs induced by Hcy was of correspondence to the miR-125b expression reduced both in vitro and in the ApoE knockout mice, the hypermethylation of p53, its decreased expression, and DNA (cytosine-5)-methyltransferase 3b (DNMT3b) up-regulated. And, we found DNMT3b is a target of miR-125b, which was verified by the Dual-Luciferase reporter assay and western blotting. Besides, the siRNA interference for DNMT3b significantly decreased the methylation level of p53, which unveiled the causative role of DNMT3b in p53 hypermethylation. miR-125b transfection further confirmed its regulative roles on p53 gene methylation status and the VSMCs proliferation. Our data suggested that a miR-125b-DNMT3b-p53 signal pathway may exist in the VSMCs proliferation induced by Hcy. (C) 2016 Elsevier Inc. All rights reserved.