lncRNA C2dat2 facilitates autophagy and apoptosis via the miR-30d-5p/DDIT4/mTOR axis in cerebral ischemia-reperfusion injury

Abstract

Cerebral ischemia-reperfusion injury (CIRI) is an important pathophysiological process of ischemic stroke associated with various physiological and pathological processes, including autophagy and apoptosis. In this study, we examined the role and mechanism of long noncoding RNA CAMK2D-associated transcript 2 (C2dat2) in regulating CIRI in vivo and in vitro . C2dat2 up-regulation facilitated neuronal autophagy and apoptosis induced by CIRI. Mechanistically, C2dat2 acts as a competing endogenous RNA (ceRNA) to negatively regulate miR-30d-5p expression. More specifically, miR-30d-5p targeted the 3′-untranslated region of DNA damage-inducible transcript 4 (DDIT4) and silenced its target mRNA DDIT4. Additionally, C2dat2 binding with heat shock cognate 70/heat shock protein 90 blocked RNA-induced silencing complex assembly to abolish the miR-30d-5p targeting of DDIT4 and inhibited miR-30d-5p to silence its target mRNA DDIT4. Further analysis showed that C2dat2 knockdown conspicuously inhibited the up-regulation of DDIT4 and Beclin-1 levels and LC3B II/I ratio and the down-regulation of P62 and phosphorylated mammalian target of rapamycin (mTOR)/mTOR and phosphorylated-P70S6K/P70S6K ratio in Neuro-2a cells after oxygen-glucose deprivation/reoxygenation. This study first revealed that C2dat2/miR-30d-5p/DDIT4/mTOR forms a novel signaling pathway to facilitate autophagy and apoptosis induced by CIRI, contributing to the better understanding of the mechanisms of CIRI and enriching the ceRNA hypothesis in CIRI.

Long non-coding RNA Plasmacytoma variant 1 in acute ischemic stroke: association with disease risk, severity, and recurrence-free survival and relation with inflammatory cytokines

“…One possible explanation could be that since knockdown of the Lnc-PVT1 could moderate the loss of neuron [4], we assumed deteriorative AIS patients' RFS might result from Lnc-PVT1 overexpression. Another explanation could be that in AIS patients, the overexpression of Lnc-PVT1 might cause a poor prognosis through interacting with the notorious adverse prognostic factors, such as ischemia/reperfusion injury [16,17]. However, the current hypothesis needed to be further verified, since related reports remained scarce.…”

miR-30d-5p: A Non-Coding RNA With Potential Diagnostic, Prognostic and Therapeutic Applications

“…miR-30d-5p targeted the 3′-UTR site of Beclin1 mRNA and participated in autophagy in a newborn rat HI brain via regulating Beclin1. The C2dat2/ miR-30d-5p/DDIT4/mTOR axis formed a new signaling pathway facilitating autophagy induced by cerebral ischemia reperfusion injury (Xu et al, 2021). Specifically, C2dat2 blocked the targeting function of miR-30d-5p on DDIT4, and promoted the upregulation of DDIT4 and Beclin-1 levels.…”

Specific microRNAs for Modulation of Autophagy in Spinal Cord Injury

“…AntagomiRs of miR-30d promoted autophagy and reduced apoptosis in post-ischemia astrocytes [ 150 ] and neonatal rat neurons [ 151 ], while another study demonstrated that miR-30d decreased neuroinflammation by reducing autophagy in macrophages and subsequently promoting M2 macrophage polarization over M1 [ 152 ]. Additionally, the sponging of miR-30b and miR-30d by lncRNAs SNHG12 (small nucleolar RNA host gene 12) and C2dat2 (CAMK2D-associated transcript 2), respectively, was shown to increase autophagy and apoptosis after cerebral ischemia–reperfusion injury [ 146 , 153 ].…”