POAG is a multifactorial disorder with various etiologies that is estimated to occur in about 52 million patients in 2020 around the world[21]. During the last few years, considerable efforts have been made to investigate the molecular mechanisms of POAG[22, 23]; however, most previous studies have mainly focused on protein-coding genes or miRNAs but not on lncRNAs[22-24].
It has been reported that more than 10,000 lncRNAs are produced by human genomes; however, to date, little information related to lncRNAs, especially their function, have been established[25, 26]. Recently, lncRNA has been found to be involved in some important regulatory processes, including transcriptional interference, transcriptional activation, and chromatin modification, and it may serve as a biomarker for various diseases, such as lung cancer[27], colorectal cancer[28], diabetes mellitus[29], and liver fibrosis[30]. Nevertheless, few studies have reported the role of lncRNA in the pathogenesis of POAG. Thus, the identification of lncRNA in the pathogenesis of POAG is necessary.
The newly emerged ceRNA hypothesis has been suggested as an innovative post-transcriptional regulatory mechanism of gene expression. Under this ceRNA network, the lncRNAs and mRNAs are connected by their common target miRNAs[30]. In recent years, several studies have explored the underlying molecular mechanisms based on the ceRNA network in some diseases, such as breast cancer[32], ischemic stroke[33], and rheumatoid arthritis[34]. To identify lncRNAs significantly associated with POAG, in this study, the mRNA and lncRNA expression profiles of POAG patients were first used and combined with miRNA-target interactions to create a ceRNA network and to investigate the potential implications of these lncRNAs in the development of POAG.
In this study, four lncRNAs (DNAJC27-AS1, AF121898, OIP5-AS1, and SNX29P2) served as the hub nodes finally. In addition, the GO and KEGG pathway analyses were used to assess enriched biological functions. The differentially expressed mRNA in the lncRNA–miRNA–mRNA ceRNA network-related GO analysis showed that ubiquitin-like protein ligase, ubiquitin protein ligase, and others could play an important role in the development of POAG. The pathway analysis further revealed that 17 unique pathways were enriched, including the MAPK signaling pathway, endocytosis pathway, and Wnt signaling pathway. In fact, an increasing amount of experimental evidence has indicated that these enriched pathways have always been involved in glaucoma. For example, Beit-Yannai et al[35]. found that AH in a rat model of induced elevated IOP expressed several signaling members of the MAPK family; they suggested that MAPKs present in the aqueous humor are a novel signal involved in glaucoma pathology. In addition, another study showed that the MAPK signal pathway participates in protecting human trabecular meshwork cells from pressure‑induced apoptosis[36]. Webber et al.[37] reported that Wnt signaling pathways play important roles in the regulation of TM homeostasis and IOP[38]. Thus, the enrichment results could suggest that the lncRNA–miRNA–mRNA ceRNA network plays an important role, by way of these pathways, in the development of POAG.
Hub nodes, which have been examined in some studies and are characterized by their high degree of connectivity to other nodes in the ceRNA network, can be used as topological properties of the ceRNA network to assess the significance of genes[39, 40]. In the present study, four lncRNAs (DNAJC27-AS1, AF121898, OIP5-AS1, and SNX29P2) were observed to be topological hub nodes whose betweenness, network degree, and closeness centrality were significantly higher in comparison with other lncRNAs. Thus far, among these hub lncRNAs, DNAJC27-AS1, AF121898, and SNX29P2 have not been reported in any study. OIP5-AS1 is an antisense lncRNA that has been reported to play a critical role in various disorders, including oral squamous cell carcinoma[41], gastric cancer[42], cardiovascular disease[43], and multiple sclerosis[44]. Li and colleague’s study revealed that OIP5-AS1 could promote the progression of oral squamous cell carcinoma by regulating the miR-338-3p/NRP1 axis[41]. Another study has also indicated an aggressive role of ceRNA to drive migration, invasion, and proliferation of human hemangioma endothelial cells via regulating the miR-195-5p/NOB1 axis[45]. In the present study, it was observed that OIP5-AS1 displayed low-expression, which could compete with miRNAs (hsa-miR-17-5p, hsa-miR-20b-5p, hsa-miR-761, hsa-miR-3619-5p, hsa-miR-24-3p, hsa-miR-27a, hsa-miR-338-3p, and hsa-miR-129-5p) to regulate target gene expression. These miRNAs interacted with OIP5-AS1 and have been known to be involved in glaucoma. For example, Zhao’s study has confirmed that miR-27a (a target miRNA of OIP5-AS1) has protective impacts on H2O2-injured human trabecular meshwork cells, which comprise a common glaucoma cell model[46]. Another miRNA (miR‑17‑5p, a target miRNA of OIP5-AS1) has been found to have the function of regulating the proliferation and apoptosis of human trabecular meshwork cells in response to oxidative stress[47]. Up to now, the research on OIP5-AS1 in glaucoma is still blank. The findings of our study show that OIP5-AS1 may be related to the development of glaucoma via lncRNA–miRNA–mRNA ceRNA network analysis. Therefore, the OIP5-AS1/miRNA/mRNA axis may become a hot issue for the study of glaucoma in the future.
Although the findings of this study have important clinical significance, the limitations should be discussed. First, the conclusion of this study based on the GEO database should be verified by other experimental evidence. Second, the precise cellular sources and mechanisms underlying hub genes, such as OIP5-AS1, DNAJC27-AS1, AF121898, and SNX29P2, in relation to POAG should be further investigated. Third, from the GEO database, 10 AH samples from POAG patients and 10 AH samples from cataract patients is a relatively small sample; this is the major drawback when performing genetic studies of association. Thus, the conclusion and the results of this study should be interpreted with caution.
In summary, during this study, a POAG-related lncRNA–miRNA–mRNA ceRNA network was constructed, and hub lncRNAs, such as OIP5-AS1, DNAJC27-AS1, AF121898, and SNX29P2, were identified in the development of POAG, which provided novel insights into exploring the underlying mechanism of POAG. Further experimental studies should be performed to elucidate the molecular mechanisms underlying the lncRNA function in POAG.