State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54S Xianlie Road, Guangzhou 510060, People's Republic of China.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 17177 Stockholm, Sweden.
Cell Death Differ. 2017 Aug;24(8):1431-1442. doi: 10.1038/cdd.2016.152. Epub 2017 Jun 16.
Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial-mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFβ2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers.
纤维化是一种涉及多种器官疾病发展和进展的慢性过程，几乎导致了所有已知死亡病例的一半。上皮-间充质转化（EMT）是器官纤维化的重要过程。晶状体因其独特的生物学特性，成为研究纤维化过程的理想生物学工具。通过获得和丧失功能的实验，以及不同的晶状体纤维化模型，我们证明了 microRNA（miR）-26a 和 miR-26b，miR-26 家族的成员，在 EMT 和纤维化中起着关键作用。它们可以显著抑制体外和体内晶状体上皮细胞增殖、迁移、EMT 和晶状体纤维化。有趣的是，我们揭示了 miR-26a 和 miR-26b 的抗 EMT 作用机制是通过直接靶向 Jagged-1 并抑制 Jagged-1/Notch 信号通路。此外，我们提供了体外和体内证据表明，Jagged-1/Notch 信号通路在 TGFβ2 刺激的 EMT 中被激活，而 Notch 信号通路的阻断可以逆转晶状体上皮细胞（LEC）的 EMT 和晶状体纤维化。鉴于 EMT 普遍参与大多数纤维化疾病、癌症转移和复发，miR-26 家族和 Notch 通路可能在治疗纤维化疾病和癌症方面具有治疗用途。
