Post-Transcriptional Regulation of Necroptosis Gene EIF2AK2 in Peripheral Blood of Bronchopulmonary Dysplasia

Abstract

Background: Bronchopulmonary dysplasia (BPD) remains the most frequent chronic lung disease among infants, characterized by multifactorial pathogenesis. Necroptosis represents a caspase-independent mode of programmed cell death, and its deregulation is associated with lung diseases, but the mechanisms of necroptosis in BPD are still unclear. This work was conducted to unveil the post-transcriptional regulatory mechanisms of necroptosis in BPD. Methods: We sequenced messenger RNA (mRNA) (BPD, n = 4; controls, n = 4) and microRNA (miRNA) (BPD, n = 5; controls, n = 5) profiles in peripheral blood specimens. The GSE125873 dataset comprising mRNA profiles from 11 BPD individuals and 10 controls was obtained. The circular RNA (circRNA)-miRNA-mRNA networks and a necroptosis-based subnetwork were constructed on the basis of the circBank and starBase databases. The diagnostic efficacy of eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) was assessed using receiver operator characteristic curve (ROC). EIF2AK2-relevant molecules were analyzed with weighted correlation network analysis (WGCNA), followed by molecular classification through consensus clustering method. In vitro experiments were conducted for validating the main findings. Results: Aberrantly expressed mRNAs and miRNAs were determined in peripheral blood of BPD relative to controls. Specifically, hsa_circ_0075945/hsa_circ_0038897/hsa_circ_0038898/hsa_circ_0041143 were found to mediate hsa-miR-143-3p, while hsa_circ_0075924/hsa_circ_0075925/hsa_circ_0033776/hsa_circ_0089761 were associated with hsa-miR-589-5p, both of which post-transcriptionally regulated EIF2AK2 expression. EIF2AK2 can effectively diagnose BPD (area under the curve (AUC) = 0.938). Thirty-one EIF2AK2-related genes were selected, which classified BPD into two molecular subtypes. EIF2AK2 knockdown alleviated apoptosis of hyperoxia-induced BEAS-2B cells (p < 0.0001). Conclusions: Collectively, necroptosis gene EIF2AK2 acts as a molecular determinant of BPD, and our findings uncover the contribution of post-transcriptional regulation to its aberrant expression.