lncRNA AK054386 Functions as a ceRNA to Sequester miR-199 and Induce Sustained Endoplasmic Reticulum Stress in Hepatic Reperfusion Injury

Abstract

Hepatic ischemia-reperfusion injury (IRI) is a very complex pathological process that is often associated with liver trauma and surgery, especially liver transplantation surgery. Although endoplasmic reticulum stress (ERS) plays a role in this process, the posttranscriptional regulators and the underlying mechanisms are still unclear. Here, we report that the lncRNA AK054386 was increased in hepatic IRI models. Furthermore, AK054386 can act as a “competing endogenous RNA (ceRNA)” and regulate ERS-related factors by binding and sequestering miR-199, which was shown to inhibit ERS in our previous report. Increased expression of AK054386, which might be mediated by activated NF-κB, resulted in sustained ERS and increased cell apoptosis and death in hepatic IRI mouse and cellular models. In contrast, AK054386 inhibition had protective effects on these models. Our data indicate that AK054386 and miR-199 are critical players in hepatic IRI, and we broadened the scope regarding ceRNA mechanisms. We hope that our results will improve the understanding of hepatic IRI and may provide potential therapeutic targets.

Long Noncoding RNA/Circular RNA-miRNA-mRNA Axes in Ischemia-Reperfusion Injury

“…These results indicated that MEG3 protected hepatocytes from hepatic IRI through miR-34a/Nrf2. Furthermore, Dai et al [ 124 ] found that the levels of AK054386, miR-199, and CHOP (C/EBP homologous protein) were elevated, decreased, and elevated in hepatic IRI models, respectively. Overexpression of AK054386 promoted cell apoptosis in the BNL-CL2 IRI cell model and CHOP expression, which were rescued by miR-199 overexpression.…”

Overlapping mechanisms of lncRNA and expanded microsatellite RNA

“…Following this, H19 sequesters mir‐200b/c resulting in upregulation of the MET‐associated protein GIT2 (Zhou et al, 2017). Another study has shown a ceRNA relationship in which upregulation of the lncRNA AK054386 during hepatic ischemia–reperfusion injury depletes functional miR‐199 leading to sustained endoplasmic reticulum stress and subsequent cell death that was demonstrated in both cell culture and in mice (Dai et al, 2019). Numerous other studies have identified lncRNA‐ceRNA relationships both in cells (Kong et al, 2019; Ma et al, 2019; Qu et al, 2016) and in vivo (Guo et al, 2015).…”

The Dietary Supplement γ‐Oryzanol Attenuates Hepatic Ischemia Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress and HMGB1/NLRP3 Inflammasome

“…In recent years, it has been found that endoplasmic reticulum (ER) stress plays an important role in early HIRI [4]. Hypoxia and ATP deficiency, calcium overload, reactive oxygen species (ROS), and other factors can trigger ER stress response [5]. In order to restore normal ER function to solve organelle dysfunction, the unfolded protein response (UPR) is activated [6].…”