Department of Neurosurgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine (Jinhua Municipal Central Hospital), Jinhua, 321000, Zhejiang, China.
Department of Orthopaedics, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, Jiangsu, China; Department of Spine Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
Neurochem Int. 2021 Jul;147:104977. doi: 10.1016/j.neuint.2021.104977. Epub 2021 Jan 30.
Multiple evidence has shown that long non-coding RNAs (lncRNAs) are novel modulators in the development of many neurological diseases, including spinal cord injury (SCI). Recently, a novel lncRNA zinc finger antisense 1 (ZFAS1) has been found to facilitate the development of many human diseases. However, the effect of ZFAS1 in SCI has not been explored. In the present study, we used the SCI mouse models and LPS-treated BV-2 cellular models to explore the role of ZFAS1 in SCI. Basso Mouse Scale score was applied to reveal locomotor function. Cresyl violet staining was used to reveal volume of spared myelin around the lesion in the injured cord. RIP and luciferase reporter assay were applied to detect binding capacity among RNAs. Next, ZFAS1 was identified to be upregulated in spinal cord tissues of SCI mice. ZFAS1 knockdown promoted functional recovery and inhibited cell apoptosis and the inflammatory response in SCI mice. ZFAS1 bound with microRNA 1953 (miR-1953), and miR-1953 was downregulated in spinal cord tissues of SCI mice. Furthermore, we confirmed that ZFAS1 promoted SCI progression via binding with miR-1953. In addition, phosphatase and tensin homolog (PTEN) was verified to be a downstream target for miR-1953 in vitro, and PTEN was upregulated in spinal cord tissues of SCI mice. Finally, we illustrated that ZFAS1 inactivated the PI3K/AKT pathway through upregulation of PTEN. In conclusion, our study revealed that ZFAS1 facilitated SCI by binding with miR-1953 and regulating the PTEN/PI3K/AKT pathway, which may provide a potential novel insight for treatment of SCI.
大量证据表明，长链非编码 RNA（lncRNA）是包括脊髓损伤（SCI）在内的许多神经疾病发展中的新型调节因子。最近，一种新型 lncRNA 锌指反义 1（ZFAS1）被发现可促进许多人类疾病的发展。然而，ZFAS1 在 SCI 中的作用尚未被探索。在本研究中，我们使用 SCI 小鼠模型和 LPS 处理的 BV-2 细胞模型来探索 ZFAS1 在 SCI 中的作用。Basso 小鼠步态评分用于揭示运动功能。台盼蓝染色用于显示损伤脊髓中病变周围保留髓鞘的体积。RIP 和荧光素酶报告基因检测用于检测 RNA 之间的结合能力。接下来，ZFAS1 在 SCI 小鼠的脊髓组织中被鉴定为上调。ZFAS1 敲低可促进 SCI 小鼠的功能恢复，并抑制细胞凋亡和炎症反应。ZFAS1 与 microRNA 1953（miR-1953）结合，而 miR-1953 在 SCI 小鼠的脊髓组织中下调。此外，我们证实 ZFAS1 通过与 miR-1953 结合促进 SCI 进展。此外，在体外，磷酸酶和张力蛋白同源物（PTEN）被证实是 miR-1953 的下游靶标，并且在 SCI 小鼠的脊髓组织中上调。最后，我们说明了 ZFAS1 通过上调 PTEN 使 PI3K/AKT 通路失活。总之，我们的研究表明，ZFAS1 通过与 miR-1953 结合并调节 PTEN/PI3K/AKT 通路促进 SCI，这可能为 SCI 的治疗提供新的潜在见解。
