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Hsp90-associated DNA replication checkpoint protein and proteasome-subunit components are involved in the age-related macular degeneration

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Chinese Medical Journal 2021年第19期134卷 2322-2332页

作者： Chen Xing Xiao-Feng Liu Chun-Feng Zhang Liu Yang Department of Ophthalmology Peking University First HospitalBeijing 100034China Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education) Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital&InstituteBeijing 100142China Department of Medical Genetics School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China

Background: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.Methods: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.Results: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.Conclusions: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

关键词： Age-related macular degeneration Retinal pigment epithelium Cell senescence HSP90AA1 DNA damage checkpoint proteasomal subunit components

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