The lncRNA TUG1 regulates Smac/DIABLO expression by competitively inhibiting miR-29b and modulates the apoptosis of lens epithelial cells in age-related cataracts

As one of the first discovered lncRNAs, TUG1 has been reported to be widely expressed in a variety of tumours. It promotes cell proliferation, differentiation, apoptosis and migration. However, our understanding of its importance in cataracts is limited. This study aims to explore the mechanism by which TUG1 mediates the apoptosis of lens epithelial cells by regulating the miR-29b/Smac axis in age-related cataracts and to identify more strategies for the nonsurgical treatment of cataracts. In this experiment we found TUG1 and Smac were expressed at high levels in age-related cataract (ARC) samples and HLEB3 cells treated with H2O2, while miR-29b expression was decreased. In vitro cell-based experiments confirmed that the downregulation of TUG1 inhibits lens epithelial cell apoptosis. Mechanistically, Smac expression is negatively regulated by miR-29b. TUG1 competitively inhibits miR-29b expression and causes the release of more Smac. In addition, miR-29b reverses the effect of TUG1 on HLE-B3 cells. In conclusion, lncRNATUG1 increases Smac expression by competitively inhibiting miR-29b and promoting the apoptosis of lens epithelial cells in age-related cataracts. This mechanism is the cytological basis of ARC formation. Based on these results, the TUG1-miR29b-Smac axis may be a new molecular pathway to regulate the development of age-related cataracts.

作为首批被发现的长链非编码RNA（long non-coding RNA, lncRNA）之一，TUG1已被报道在多种肿瘤中广泛表达，可促进细胞增殖、分化、凋亡与迁移。然而，目前学界对其在白内障中的作用重要性认知仍较为有限。本研究旨在探索年龄相关性白内障（age-related cataracts, ARC）中，TUG1通过调控微小RNA-29b（microRNA-29b, miR-29b）/Smac轴介导晶状体上皮细胞凋亡的分子机制，并为白内障的非手术治疗挖掘更多潜在策略。本实验发现，在年龄相关性白内障（ARC）样本及经过氧化氢（hydrogen peroxide, H₂O₂）处理的HLEB3细胞中，TUG1与Smac均呈高表达，而miR-29b的表达水平显著下调。体外细胞实验证实，下调TUG1的表达可抑制晶状体上皮细胞的凋亡。从分子机制来看，Smac的表达受miR-29b负向调控；TUG1可通过竞争性结合机制抑制miR-29b的表达，进而促使更多Smac释放。此外，miR-29b可逆转TUG1对HLEB3细胞产生的生物学效应。综上，在年龄相关性白内障中，长链非编码RNA TUG1可通过竞争性抑制miR-29b的表达，上调Smac的表达水平，进而促进晶状体上皮细胞的凋亡，该机制乃是年龄相关性白内障发生的细胞学基础。基于上述研究结果，TUG1-miR-29b-Smac轴有望成为调控年龄相关性白内障发生发展的全新分子通路。