microRNA-4532 inhibition protects human lens epithelial cells from ultra-violet-induced oxidative injury via activating SIRT6-Nrf2 signaling
microRNA-4532 inhibition protects human lens epithelial cells from ultra-violet-induced oxidative injury via activating SIRT6-Nrf2 signaling
复制标题
microRNA-4532 抑制通过激活 SIRT6-Nrf2 信号传导保护人晶状体上皮细胞免受紫外线诱导的氧化损伤
DOI：
10.1016/j.bbrc.2019.05.026
复制
发表时间：
2019-06-30
影响因子：
3.1
通讯作者：
Jiang, Qin
中科院分区：
文献类型：
--
作者：
Sun, Guang-li;Huang, Dan;Jiang, Qin
紫外线辐射（UVR）可引起人透镜上皮细胞（HLEC）明显的氧化损伤。Sirtuin 6（SIRT 6）被证明直接结合Nrf 2，Nrf 2信号激活所必需的。在本研究中，我们发现microRNA-4532（miR-4532）靶向SIRT 6调节HLEC中的Nrf 2信号传导。HLEC中miR-4532的异位过表达降低了SIRT 6 3 '-UTR活性，导致SIRT 6下调和Nrf 2信号传导抑制。相反，通过慢病毒构建体抑制miR-4532增强SIRT 6 3 '-UTR活性、SIRT 6表达和Nrf 2信号传导激活。功能研究表明，miR-4532过表达、Nrf 2缺失或SIRT 6 shRNA增强了UVR诱导的HLEC细胞毒性和凋亡。相反，miR-4532抑制或异位SIRT 6过表达减弱了HLEC中UVR诱导的氧化损伤。重要的是，miR-4532过表达或抑制在SIRT 6-KO或Nrf 2-KO HLEC中无效。综上所述，结果表明，抑制miR-4532通过激活SIRT 6-Nrf 2途径保护HLEC免受UVR诱导的氧化损伤。靶向miR-4532-SIRT 6-Nrf 2通路可能是保护HLEC免受UVR和其他可能的氧化应激的新策略。(C)2019爱思唯尔公司All rights reserved.
Ultra-violet radiation (UVR) can induce significant oxidative injury to human lens epithelial cells (HLECs). Sirtuin 6 (SIRT6) is shown to directly bind to Nrf2, essential for Nrf2 signaling activation. In the present study, we show that microRNA-4532 (miR-4532) targets SIRT6 to regulate Nrf2 signaling in HLECs. Ectopic overexpression of miR-4532 in HLECs decreased SIRT6 3'-UTR activity, causing SIRT6 down regulation and Nrf2 signaling inhibition. Conversely, miR-4532 inhibition, by a lentiviral construct, enhanced SIRT6 3'-UTR activity, SIRT6 expression and Nrf2 signaling activation. Functional studies show that UVR-induced cytotoxicity and apoptosis in HLECs were potentiated by miR-4532 overexpression, Nrf2 depletion or SIRT6 shRNA. Conversely, miR-4532 inhibition or ectopic SIRT6 overexpression attenuated UVR-induced oxidative injury in HLECs. Importantly, miR-4532 overexpression or inhibition was ineffective in SIRT6-KO or Nrf2-KO HLECs. Taken together, the results show that inhibition of miR-4532 protects HLECs from UVR-induced oxidative injury via activation of SIRT6-Nrf2 pathway. Targeting the miR-4532-SIRT6-Nrf2 pathway could be a novel strategy to protect HLECs from UVR and possible other oxidative stresses. (C) 2019 Elsevier Inc. All rights reserved.