Jiang Qin, Zhou Changlin, Bi Zhigang, Wan Yinsheng
Department of Ophthalmology, Nanjing Medical University, Nanjing, China.
J Ocul Pharmacol Ther. 2006 Apr;22(2):93-102. doi: 10.1089/jop.2006.22.93.
Cataract is considered as the most common cause of blindness, which is curable only by surgery. Postsurgery, however, many patients gradually develop the complication of posterior capsule opacification (PCO) or secondary cataract, arising from stimulated cell proliferation and cell migration within the lens capsule. The migration of human lens epithelial cells (HLECs) plays crucial roles in the remodeling of lens capsule and cataract formation, but less is known about the cell-signaling mechanism of migration. We observed that epithelial growth factor (EGF) induced cell migration in cultured human lens epithelial cells through the ERK and PI3K/AKT pathways. EGF induced cell migration in a dose-dependent manner; EGF-induced EGFR phosphorylation and downstream activation of c-Jun N-terminal protein kinase (JNK), p38 MAP kinase (p38), extracellular signal-regulated kinase (ERK1/2) and AKT, were inhibited by PD153035 (EGFR inhibitor), JNKi (JNK inhibitor), SB203580 (p38 inhibitor), U0126 (MEK/ERK inhibitor), and LY294002 (PI3K/AKT inhibitor), respectively. Furthermore, we found that EGF induced activity of matrix metalloproteinase-2 (MMP-2) in cultured HLECs. EGF-induced MMP-2 activity was significantly inhibited by treatment of PD153035, U0126, and LY294002, but not SB203580 and JNK inhibitor, suggesting that ERK and the phosphatidylinositol-3-kinase (PI3K)/AKT pathways selectively mediate EGF-stimulated MMP-2 activity and cell migration in cultured HLECs in vitro. Taken together, our results suggest that the cell-signaling pathways involved in EGF-stimulated cell migration may constitute potential therapeutic targets in the treatment of PCO.
白内障被认为是导致失明的最常见原因，只有通过手术才能治愈。然而，术后许多患者会逐渐出现后囊膜混浊（PCO）或继发性白内障并发症，这是由晶状体囊内细胞增殖和细胞迁移受刺激引起的。人晶状体上皮细胞（HLECs）的迁移在晶状体囊重塑和白内障形成中起关键作用，但关于其迁移的细胞信号机制知之甚少。我们观察到，表皮生长因子（EGF）通过ERK和PI3K/AKT途径诱导培养的人晶状体上皮细胞迁移。EGF以剂量依赖的方式诱导细胞迁移；PD153035（EGFR抑制剂）、JNKi（JNK抑制剂）、SB203580（p38抑制剂）、U0126（MEK/ERK抑制剂）和LY294002（PI3K/AKT抑制剂）分别抑制了EGF诱导的EGFR磷酸化以及c-Jun N端蛋白激酶（JNK）、p38丝裂原活化蛋白激酶（p38）、细胞外信号调节激酶（ERK1/2）和AKT的下游激活。此外，我们发现EGF诱导培养的HLECs中基质金属蛋白酶-2（MMP-2）的活性。PD153035、U0126和LY294002处理可显著抑制EGF诱导的MMP-2活性，但SB203580和JNK抑制剂则无此作用，这表明ERK和磷脂酰肌醇-3-激酶（PI3K）/AKT途径在体外选择性介导EGF刺激的培养HLECs中MMP-2活性和细胞迁移。综上所述，我们的结果表明，参与EGF刺激细胞迁移的细胞信号通路可能构成治疗PCO的潜在治疗靶点。
