Department of Ophthalmology, Peking University First Hospital, Beijing 100034, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Hepatopancreatobiliary Surgery Department I, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Chin Med J (Engl). 2021 Sep 20;134(19):2322-2332. doi: 10.1097/CM9.0000000000001773.
Age-related macular degeneration (AMD) is the leading cause of vision loss worldwide. However, the mechanisms involved in the development and progression of AMD are poorly delineated. We aimed to explore the critical genes involved in the progression of AMD.
The differentially expressed genes (DEGs) in AMD retinal pigment epithelial (RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564, which were downloaded from the gene expression omnibus database. The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The hub genes were identified from these DEGs through protein-protein interaction network analyses. The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866. Following the identification of AMD-related key genes, the potential small molecule compounds targeting the key genes were predicted by PharmacoDB. Finally, a microRNA-gene interaction network was constructed.
Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples. These DEGs were primarily enriched in the pathways involved in the regulation of DNA replication, cell cycle, and proteasome-mediated protein polyubiquitination. Among the top ten hub genes, HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 were upregulated in the senescent ARPE-19 cells. Additionally, the drugs targeting HSP90AA1, CHEK1, and PSMA4 were identified. We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE.
Based on our findings, HSP90AA1 is likely to be a central gene controlling the DNA replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD. Targeting HSP90AA1, CHEK1, PSMA4, PSMD4, and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD through attenuating RPE senescence.
年龄相关性黄斑变性（AMD）是全球范围内导致视力丧失的主要原因。然而，AMD 发展和进展中涉及的机制仍不清楚。我们旨在探索 AMD 进展中涉及的关键基因。
使用从基因表达综合数据库下载的微阵列数据集 GSE99248 和 GSE125564，鉴定 AMD 视网膜色素上皮（RPE）/脉络膜组织中的差异表达基因（DEGs）。筛选来自两个数据集的重叠 DEGs，通过基因本体和京都基因与基因组百科全书富集分析鉴定 DEG 相关的生物学途径。通过蛋白质-蛋白质相互作用网络分析从这些 DEGs 中确定枢纽基因。用 FK866 诱导 ARPE-19 衰老后，通过定量实时聚合酶链反应评估枢纽基因的表达水平。确定 AMD 相关关键基因后，通过 PharmacoDB 预测针对关键基因的潜在小分子化合物。最后，构建 miRNA-基因相互作用网络。
微阵列分析鉴定出 AMD RPE 与健康 RPE 样本相比有 174 个 DEGs。这些 DEGs 主要富集在参与 DNA 复制、细胞周期和蛋白酶体介导的蛋白质多泛素化调节的途径中。在十大枢纽基因中，HSP90AA1、CHEK1、PSMA4、PSMD4 和 PSMD8 在衰老的 ARPE-19 细胞中上调。此外，还鉴定了针对 HSP90AA1、CHEK1 和 PSMA4 的药物。我们假设 Hsa-miR-16-5p 可能靶向 AMD RPE 中五个关键 DEG 中的四个。
根据我们的发现，HSP90AA1 可能是控制 AMD 进展中 RPE 衰老过程中 DNA 复制和蛋白酶体介导的多泛素化的核心基因。通过特定的 miRNA 或小分子靶向 HSP90AA1、CHEK1、PSMA4、PSMD4 和/或 PSMD8 基因可能通过减轻 RPE 衰老来潜在缓解 AMD 的进展。
