Involvement of endoplasmic reticulum stress and p53 in lncRNA MEG3-induced human hepatoma HepG2 cell apoptosis

Abstract

Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes. Although downregulation of lncRNA maternally expressed gene 3 (MEG3) has been identified in several types of cancers, little is known concerning its biological role and regulatory mechanism in hepatoma. Our previous studies demonstrated that MEG3 induces apoptosis in a p53-dependent manner. The aim of the present study was to determine whether endoplasmic reticulum (ER) stress is involved in MEG3‑induced apoptosis. Recombinant lentiviral vectors containing MEG3 (Lv‑MEG3) were constructed and transfected into HepG2 cells. A 3‑(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, RT‑PCR, flow cytometry, western blot analysis, immunofluorescence and immunohistochemistry were applied. Transfected HepG2 cells were also transplanted into nude mice, and the tumor growth curves were determined. The results showed that the recombinant lentivirus of MEG3 was transfected successfully into the HepG2 cells and the expression level of MEG3 was significantly increased. Ectopic expression of MEG3 inhibited HepG2 cell proliferation in vitro and in vivo, and also induced apoptosis. Ectopic expression of MEG3 increased ER stress‑related proteins 78‑kDa glucose‑regulated protein (GRP78), inositol‑requiring enzyme 1 (IRE1), RNA‑dependent protein kinase‑like ER kinase (PERK), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), caspase‑3, as well as p53 and NF‑κB expression accompanied by NF‑κB translocation from the cytoplasm to the nucleus. Furthermore, inhibition of NF‑κB with Bay11‑7082 decreased p53 expression in the MEG3‑transfected cells. These results indicate that MEG3 inhibits cell proliferation and induces apoptosis, partially via the activation of the ER stress and p53 pathway, in which NF‑κB signaling is required for p53 activation in ER stress.

Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

“…Previous studies have suggested that MEG3 increased the p53 activity in cancer cells [24, 25]. Because pulmonary hypertension and cancers have similar pathological processes, like cell proliferation increased and apoptosis decreased.…”

Identification of cancer risk lncRNAs and cancer risk pathways regulated by cancer risk lncRNAs based on genome sequencing data in human cancers

“…As lncRNAs may be pivotal in many biochemical pathways20, we explored whether cancer risk lncRNAs from different cancer datasets display a similar regulation pattern with their cancer risk pathways or not. A total of 23 lncRNAs which involved in the regulation of cancer risk pathways were identified as cancer risk lncRNAs in the six cancer datasets.…”

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes

“…In addition, some studies have shown that lncRNAs influence the UPR. Overexpression of lncRNA MEG3 has been documented to induce ER stress markers (eg, IRE1α) and also induces apoptosis in human hepatoma cells, 23 whereas gain of function of lncRNA TUG1 partly blocked ER stress pathways and was organ protective in a model of cold-induced liver injury in mice. 24 ER stress affects multiple cellular processes and may result in adaptive or proapoptotic pathways.…”

“…16 To date, only few lncRNAs have been shown to be associated with the unfolded protein response (UPR). [22][23][24] Kato et al 22 recently demonstrated that lnc-MGC, which is induced by ER stress, is upregulated in a mouse model of diabetic nephropathy. In addition, some studies have shown that lncRNAs influence the UPR.…”