Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU), 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
Department of Chemical Engineering, Institute for Medical Engineering and Science, David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Cell Death Dis. 2018 May 24;9(6):632. doi: 10.1038/s41419-018-0690-y.
MicroRNAs (miRs) contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by a miR. We demonstrate that genotoxic stress-induced miR-494 inhibits the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Gain- and loss-of-function experiments show that miR-494 exacerbates DNA damage and drives endothelial senescence. Increase of miR-494 affects telomerase activity, activates p21, decreases pRb pathways, and diminishes angiogenic sprouting. Genetic and pharmacological disruption of the MRN pathway decreases VEGF signaling, phenocopies miR-494-induced senescence, and disrupts angiogenic sprouting. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.
微小 RNA（miRs）通过缓冲细胞过程免受外部干扰，从而有助于生物稳健性。在这里，我们报告了 DNA 损伤反应和血管生成信号之间的意外联系，这种联系受到 miR 的缓冲。我们证明，致瘤应激诱导的 miR-494 通过靶向 MRE11a-RAD50-NBN（MRN）复合物来抑制 DNA 修复机制。增益和功能丧失实验表明，miR-494 加剧 DNA 损伤并驱动内皮细胞衰老。miR-494 的增加会影响端粒酶活性，激活 p21，降低 pRb 通路，并减少血管生成芽生。MRN 通路的遗传和药理学破坏会降低 VEGF 信号，模拟 miR-494 诱导的衰老，并破坏血管生成芽生。血管靶向递送 miR-494 可减少生长因子诱导的和肿瘤血管生成在小鼠模型中。我们的工作确定了一种潜在的 miR 促进机制，通过该机制，内皮细胞可以免受 VEGF 信号的影响，从而促进衰老的发生，并强调了靶向 DNA 修复以破坏病理性血管生成的潜力。
