Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation.
Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation.
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DOI：
10.1038/cddis.2017.73
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发表时间：
2017-03-02
影响因子：
9
通讯作者：
Cho NH
中科院分区：
文献类型：
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作者：
Kim BG;Gao MQ;Kang S;Choi YP;Lee JH;Kim JE;Han HH;Mun SG;Cho NH
肿瘤生长产生机械压缩，这可能触发癌症和基质细胞中的机械转导并促进肿瘤进展。然而，人们对压缩如何刺激信号传导并促进肿瘤进展知之甚少。在本研究中，我们使用体外压缩模型证明了压缩增强了肿瘤进展表型，并验证了高压缩和低压缩乳腺癌组织体外模型的结果。在MDA-MB-231和BT-474乳腺癌细胞系和癌症相关成纤维细胞中，机械压缩通过DNMT 3A依赖性启动子甲基化诱导miR-9下调。miR-9下调可诱导miR-9靶基因（LAMC 2、ITGA 6和EIF 4 E）的过表达，最终增强血管内皮生长因子的产生。去甲基化和减压可以逆转压缩诱导的miR-9下调以及随后的miR-9靶基因和VEGFA过表达。
Tumor growth generates mechanical compression, which may trigger mechanotransduction in cancer and stromal cells and promote tumor progression. However, very little is known about how compression stimulates signal transduction and contributes to tumor progression. In the present study, we demonstrated that compression enhances a tumor progression phenotype using an in vitro compression model, and validated the results from the in vitro model with high- and low-compressed breast cancer tissues. Mechanical compression induced miR-9 downregulation by DNMT3A-dependent promoter methylation in the MDA-MB-231 and BT-474 breast cancer cell lines and in cancer-associated fibroblasts. The overexpression of miR-9 target genes (LAMC2, ITGA6, and EIF4E) was induced by miR-9 downregulation, which eventually enhanced vascular endothelial growth factors production. Demethylation and decompression could reverse compression-induced miR-9 downregulation and following overexpression of miR-9 target genes and VEGFA.