Long Noncoding RNA THAP9‐AS1 and TSPOAP1‐AS1 Provide Potential Diagnostic Signatures for Pediatric Septic Shock

Abstract

Background. Sepsis is a systemic inflammatory syndrome caused by infection with a high incidence and mortality. Although long noncoding RNAs have been identified to be closely involved in many inflammatory diseases, little is known about the role of lncRNAs in pediatric septic shock. Methods. We downloaded the mRNA profiles GSE13904 and GSE4607, of which GSE13904 includes 106 blood samples of pediatric patients with septic shock and 18 health control samples; GSE4607 includes 69 blood samples of pediatric patients with septic shock and 15 health control samples. The differentially expressed lncRNAs were identified through the limma R package; meanwhile, GO terms and KEGG pathway enrichment analysis was performed via the clusterProfiler R package. The protein-protein interaction (PPI) network was constructed based on the STRING database using the targets of differently expressed lncRNAs. The MCODE plug-in of Cytoscape was used to screen significant clustering modules composed of key genes. Finally, stepwise regression analysis was performed to screen the optimal lncRNAs and construct the logistic regression model, and the ROC curve was applied to evaluate the accuracy of the model. Results. A total of 13 lncRNAs which simultaneously exhibited significant differences in the septic shock group compared with the control group from two sets were identified. According to the 18 targets of differentially expressed lncRNAs, we identified some inflammatory and immune response-related pathways. In addition, several target mRNAs were predicted to be potentially involved in the occurrence of septic shock. The logistic regression model constructed based on two optimal lncRNAs THAP9-AS1 and TSPOAP1-AS1 could efficiently separate samples with septic shock from normal controls. Conclusion. In summary, a predictive model based on the lncRNAs THAP9-AS1 and TSPOAP1-AS1 provided novel lightings on diagnostic research of septic shock.

Stress induced Differential Expression of THAP9 & THAP9-AS1 in the S-phase of cell cycle

“…THAP9-AS1 is a recently annotated lncRNA and has been shown to be upregulated in pancreatic cancer and neutrophil apoptosis and downregulated in case of septic shock (35)(36)(37) . In this study, we have quantified THAP9 and THAP9-AS1 transcript expression under various stress conditions in the S-phase of cell cycle.…”

“…This leads us to speculate that there exists a stress specific regulation of THAP9 and THAP9-AS1 gene-pair that switches to THAP9-AS1 under stress conditions. This also might explain the upregulation of THAP9-AS1 in cancer cells which are naturally stressed (35–37). Moreover, it is possible that both these genes play an unknown role in DNA repair and this might be responsible for their increased expression under certain stress conditions.…”

“…Antisense transcripts and their corresponding sense transcripts often show inverse expression; thus suggesting that one regulates the other (33,34) . There have been recent reports where the THAP9-AS1 lncRNA has been implicated in pancreatic cancer, septic shock and neutrophil apoptosis (35)(36)(37) . This has piqued our interests in studying the relationship between THAP9 and THAP9-AS1.…”

Long Non-Coding RNAs as Biomarkers and Therapeutic Targets in Sepsis

“…Another in vitro study demonstrated that NEAT1 was observed to regulate miR-495-3p/signal transducers and activators of transcription axis and miR-211/phosphoinositide-3-kinase/ protein kinase B axis in inflammatory process of sepsis (44). Even though the investigations for the roles of lncRNAs in septic shock are lacking, Wu et al identified lncRNA THAP9-AS1 and TSPOAP1-AS1 that might be of practical values for pediatric septic shock diagnosis (45). What is more interesting is that some lncRNAs like MALAT1, NEAT1, CRNDE, TUG1, and HOTAIR could exert therapeutic or diagnostic influence across different organ systems (Figure 1).…”

“…Even though the investigations for the roles of lncRNAs in septic shock are lacking, Wu et al. identified lncRNA THAP9-AS1 and TSPOAP1-AS1 that might be of practical values for pediatric septic shock diagnosis ( 45 ). What is more interesting is that some lncRNAs like MALAT1, NEAT1, CRNDE, TUG1, and HOTAIR could exert therapeutic or diagnostic influence across different organ systems ( Figure 1 ).…”