Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada; Institute of Animal Nutrition, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu, 611130 Sichuan, China; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12 Islamabad, Pakistan.
Mol Ther. 2017 Sep 6;25(9):2062-2074. doi: 10.1016/j.ymthe.2017.05.022. Epub 2017 Jul 1.
Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically.
伤口愈合延迟或受损是一个全球性的主要健康问题，特别是在糖尿病和动脉粥样硬化患者中。在这里，我们展示了环状 RNA circ-Amotl1 的表达加速了小鼠切口模型中的愈合过程。进一步的研究表明，外源性 circ-Amotl1 增加了 Stat3 和 Dnmt3a 的蛋白水平。增加的 Dnmt3a 随后使 microRNA miR-17 的启动子甲基化，降低 miR-17-5p 的水平，但增加纤连蛋白的表达。我们发现 Stat3 与 Dnmt3a 和纤连蛋白相似，是 miR-17-5p 的靶标。miR-17-5p 水平降低会增加纤连蛋白、Dnmt3a 和 Stat3 的表达。所有这些都导致细胞黏附、迁移、增殖、存活和伤口修复增加。此外，我们发现 circ-Amotl1 不仅增加了 Stat3 的表达，还促进了 Stat3 的核转位。因此，外源性表达的 circ-Amotl1 和 Stat3 主要被转运到细胞核。在 circ-Amotl1 的存在下，Stat3 与 Dnmt3a 启动子的结合亲和力增加，促进 Dnmt3a 的转录。外源性应用 circ-Amotl1 加速伤口修复可能为临床皮肤伤口愈合提供新的思路。
