Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer.
Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer.
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DOI：
10.1186/1471-2164-15-s11-s3
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发表时间：
2014
期刊：
影响因子：
4.4
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Zhou H;Chen JX;Yang CS;Yang MQ;Deng Y;Wang H
表没食子儿茶素没食子酸酯（Epigallocatechin-3-gallate，EGCG）具有抗氧化活性，并通过结合特异性蛋白质调节细胞功能，从而抑制肿瘤细胞的生长。我们先前证明，EGCG通过结合HIF-1α上调microRNA（即miR-210）的表达，导致细胞增殖减少和锚定非依赖性生长。然而，在给予高剂量EGCG的实验动物中，EGCG与HIF-1α和许多其他靶点的结合亲和力高于EGCG血浆峰值水平，这引起了人们对HIF-1α对microRNA的调节是否参与EGCG体内抗癌活性的关注。我们采用功能基因组学方法来阐明microRNA在EGCG抑制烟草致癌物诱导的A/J小鼠肺肿瘤中的作用。通过分析microRNA谱，我们发现21种microRNA的表达水平发生了适度的变化。通过计算方法将这21个microRNA与mRNA表达谱相关联，我们确定了26个潜在的靶基因。进一步的通路分析显示，EGCG对AKT、NF-κB、MAP激酶和细胞周期的调控网络影响最大，而所鉴定的miRNA靶点则参与了AKT、MAP激酶和细胞周期的调控网络。这些结果表明，miRNA介导的调控积极参与了EGCG体内抗癌活性的主要方面。
Epigallocatechin-3-gallate (EGCG) has been demonstrated to inhibit cancer in experimental studies through its antioxidant activity and modulations on cellular functions by binding specific proteins. We demonstrated previously that EGCG upregulates the expression of microRNA (i.e. miR-210) by binding HIF-1α, resulting in reduced cell proliferation and anchorage-independent growth. However, the binding affinities of EGCG to HIF-1α and many other targets are higher than the EGCG plasma peak level in experimental animals administered with high dose of EGCG, raising a concern whether the microRNA regulation by HIF-1α is involved in the anti-cancer activity of EGCG in vivo. We employed functional genomic approaches to elucidate the role of microRNA in the EGCG inhibition of tobacco carcinogen-induced lung tumors in A/J mice. By analysing the microRNA profiles, we found modest changes in the expression levels of 21 microRNAs. By correlating these 21 microRNAs with the mRNA expression profiles using the computation methods, we identified 26 potential targeted genes of the 21 microRNAs. Further exploration using pathway analysis revealed that the most impacted pathways of EGCG treatment are the regulatory networks associated to AKT, NF-κB, MAP kinases, and cell cycle, and the identified miRNA targets are involved in the networks of AKT, MAP kinases and cell cycle regulation These results demonstrate that the miRNA-mediated regulation is actively involved in the major aspects of the anti-cancer activity of EGCG in vivo.