State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, People's Republic of China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, People's Republic of China.
Biochem Biophys Res Commun. 2019 Apr 2;511(2):336-342. doi: 10.1016/j.bbrc.2019.02.049. Epub 2019 Feb 18.
Epithelial-mesenchymal transition (EMT) is the main cause of fibrotic cataracts. Oxidative stress was recently shown to trigger epithelial-mesenchymal transition in human lens epithelial cells (hLECs). However, the underlying mechanism is not fully understood. Here we reported that exposure to low doses (100 μM) of HO led to EMT in hLECs, as indicated by simultaneous down-regulated of E-cadherin and ZO-1, and up-regulated of alpha smooth muscle actin (α-SMA). HO-induced EMT was accompanied by accumulation of phosphorylated JNK1. In contrast, knockdown of JNK1 via siRNA reversed HO-induced EMT. Of interest, in human lens capsules of anterior subcapsule cataracts, the expressions of JNK1, as well as β-catenin and its downstream effectors cyclin D and c-Myc, were augmented compared to that in normal lens capsules. Mechanistically, activated JNK1 dislodged β-catenin from the cell membrane, which subsequently translocated to the nuclei and triggered transcription of its effectors. Nuclei β-catenin, cyclin D and c-Myc were accumulated in HO-induced EMT and JNK1 depletion abrogated these trend in hLECs. In conclusion, our data suggest that JNK1 is essential for HO-induced EMT in hLECs via mediating the translocation of β-catenin.
上皮-间充质转化（EMT）是纤维性白内障的主要原因。最近的研究表明，氧化应激可引发人晶状体上皮细胞（hLEC）发生 EMT。然而，其潜在的机制尚不完全清楚。在此，我们报道了低剂量（100μM）HO 可导致 hLEC 发生 EMT，表现为 E-钙黏蛋白和 ZO-1 同时下调，α 平滑肌肌动蛋白（α-SMA）上调。HO 诱导的 EMT 伴随着 JNK1 的磷酸化积累。相反，通过 siRNA 敲低 JNK1 可逆转 HO 诱导的 EMT。有趣的是，在人晶状体前囊下白内障的前囊内，与正常晶状体囊相比，JNK1 以及 β-连环蛋白及其下游效应物 cyclin D 和 c-Myc 的表达均增加。从机制上讲，激活的 JNK1 将 β-连环蛋白从细胞膜上解离下来，随后转移到细胞核中并触发其效应物的转录。核内 β-连环蛋白、cyclin D 和 c-Myc 在 HO 诱导的 EMT 中积累，而 JNK1 的耗竭则消除了 hLEC 中的这种趋势。综上所述，我们的数据表明，JNK1 通过介导β-连环蛋白的易位，对 hLEC 中的 HO 诱导的 EMT 是必需的。
