Non-coding RNA Maternally Expressed Gene 3 Research Articles

The Genetic Variants of Long Noncoding RNA MEG3 and Its Association to the Clinical Features of Diabetic Retinopathy

Purpose This study aimed to investigate the potential correlation between the single-nucleotide polymorphism (SNP) of maternally expressed gene 3 (MEG3) and the clinical manifestations of diabetic retinopathy (DR). Methods Five loci of MEG3 SNPs including rs4081134 (G/A), rs10144253 (T/C), rs7158663 (G/A), rs3087918 (T/G) and rs11160608 (A/C) were genotyped by TaqMan allelic discrimination in 457 non-DR patients and 280 DR individuals. Results The distribution frequency of MEG3 SNP rs7158663 GA (AOR: 0.683, 95% CI: 0.478-0.975, p = 0.036) and MEG3 SNP rs7158663 GA + AA (AOR: 0.686, 95% CI: 0.487-0.968, p = 0.032) were significantly lower in the DR group. And the MEG3 SNP rs7158663 GA + AA (AOR: 0.610, 95% CI: 0.377-0.985, p = 0.043) demonstrated a significantly lower distribution frequency in the male DR group. Besides, the DR patients with MEG3 SNP rs7158663 GA + AA genotype showed a significantly lower HbA1c level than the DR patients with MEG3 SNP rs7158663 GG genotype (7.29 ± 1.23 versus 7.74 ± 1.49, p = 0.013). Moreover, in the analysis using data from gene expression data series database, a higher MEG3 level was significantly correlated to a lower miR-182 level in the database (p = 0.0114). Conclusions In this study, the distribution frequency of MEG3 SNP rs7158663 GA + AA genotype was lower in DR, while the DR would develop under lower HbA1c level in DM patients with this MEG3 SNP variant.

The role of long noncoding RNA MEG3 in fibrosis diseases.

Fibrosis is a prevalent pathological condition observed in various organs and tissues. It primarily arises from the excessive and abnormal accumulation of the extracellular matrix, resulting in the structural and functional impairment of tissues and organs, which can culminate in death. Many forms of fibrosis, including liver, cardiac, pulmonary, and renal fibrosis, are considered irreversible. Maternally expressed gene 3 (MEG3) is an imprinted RNA gene. Historically, the downregulation of MEG3 has been linked to tumor pathogenesis. However, recent studies indicate an emerging association of MEG3 with fibrotic diseases. In this review, we delve into the current understanding of MEG3's role in fibrosis, aiming to shed light on the molecular mechanisms of fibrosis and the potential of MEG3 as a novel therapeutic target.

Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m6A Methylation.

Cigarette smoke extract (CSE)-treated mouse airway epithelial cells (MAECs)-derived exosomes accelerate the progression of chronic obstructive pulmonary disease (COPD) by upregulating triggering receptor expressed on myeloid cells 1 (TREM-1); however, the specific mechanism remains unclear. We aimed to explore the potential mechanisms of CSE-treated MAECs-derived exosomes on M1 macrophage polarization and pyroptosis in COPD. In vitro, exosomes were extracted from CSE-treated MAECs, followed by co-culture with macrophages. In vivo, mice exposed to cigarette smoke (CS) to induce COPD, followed by injection or/and intranasal instillation with oe-TREM-1 lentivirus. Lung function and pathological changes were evaluated. CD68+ cell number and the levels of iNOS, TNF-α, IL-1β (M1 macrophage marker), and pyroptosis-related proteins (NOD-like receptor family pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase-1 recruitment domain, caspase-1, cleaved-caspase-1, gasdermin D [GSDMD], and GSDMD-N) were examined. The expression of maternally expressed gene 3 (MEG3), spleen focus forming virus proviral integration oncogene (SPI1), methyltransferase 3 (METTL3), and TREM-1 was detected and the binding relationships among them were verified. MEG3 increased N6-methyladenosine methylation of TREM-1 by recruiting SPI1 to activate METTL3. Overexpression of TREM-1 or METTL3 negated the alleviative effects of MEG3 inhibition on M1 polarization and pyroptosis. In mice exposed to CS, EXO-CSE further aggravated lung injury, M1 polarization, and pyroptosis, which were reversed by MEG3 inhibition. TREM-1 overexpression negated the palliative effects of MEG3 inhibition on COPD mouse lung injury. Collectively, CSE-treated MAECs-derived exosomal long non-coding RNA MEG3 may expedite M1 macrophage polarization and pyroptosis in COPD via the SPI1/METTL3/TREM-1 axis.

Long non-coding RNA MEG3 silencing weakens high glucose-induced mesangial cell injury by decreasing LIN28B expression by sponging and sequestering miR-23c.

Diabetic nephropathy (DN) is a common kidney disease in diabetic patients. Long non-coding RNA maternally expressed gene 3 (MEG3) and microRNA (miR)-23c are reported to be implicated in DN development. Nevertheless, it is unclear that the molecular mechanism between MEG3 and miR-23c in DN remains unclear. Human mesangial cells (HMCs) were treated with high glucose (HG) to simulate the DN status in vitro. Expression of MEG3 and miR-23c was measured. Effects of MEG3 silencing on HG-stimulated HMC injury were determined. The relationship between MEG3 and miR-23c was verified by the dual-luciferase reporter and RNA immunoprecipitation assays. MEG3 was overexpressed in serums from DN patients and HG-stimulated HMCs. MEG3 knockdown weakened HG-stimulated HMC proliferation, extracellular matrix (ECM) accumulation, and inflammation. MEG3 regulated lin-28 homolog B (LIN28B) expression through adsorbing miR-23c. MiR-23c inhibitor reversed MEG3 knockdown-mediated effects on HG-stimulated HMC proliferation, ECM accumulation, and inflammation. LIN28B overexpression overturned miR-23c mimic-mediated effects on HG-stimulated HMC proliferation, ECM accumulation, and inflammation. MEG3 regulated HMC injury via regulation of the miR-23c/LIN28B axis in DN, which can help us better understand the mechanism of DN mediated by MEG3.

Long Non-Coding RNA MEG3 in Metal Carcinogenesis.

Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.

The Biological Roles and Molecular Mechanisms of Long Non-Coding RNA MEG3 in the Hallmarks of Cancer.

Long non-coding RNAs (lncRNAs) are critical regulators in various biological processes involved in the hallmarks of cancer. Maternally expressed gene 3 (MEG3) is lncRNA that regulates target genes through transcription, translation, post-translational modification, and epigenetic regulation. MEG3 has been known as a tumor suppressor, and its downregulation could be found in various cancers. Furthermore, clinical studies revealed that impaired MEG3 expression is associated with poor prognosis and drug resistance. MEG3 exerts its tumor suppressive effect by suppressing various cancer hallmarks and preventing cells from acquiring cancer-specific characteristics; as it could suppress tumor cells proliferation, invasion, metastasis, and angiogenesis; it also could promote tumor cell death and regulate tumor cell metabolic reprogramming. Hence, MEG3 is a potential prognostic marker, and overexpressing MEG3 might become a potential antitumor therapeutic strategy. Herein, we summarize recent knowledge regarding the role of MEG3 in regulating tumor hallmarks as well as the underlying molecular mechanisms. Furthermore, we also discuss the clinical importance of MEG3, as well as their potential in tumor prognosis and antitumor therapeutic strategies.

Novel Contribution of Long Non-coding RNA MEG3 Genotype to Prediction of Childhood Leukemia Risk.

Acute lymphoblastic leukemia (ALL) is frequent among children. Few studies have researched the relationship between maternally expressed gene 3 (MEG3) and cancer risk. We hypothesized long non-coding RNA MEG3 polymorphisms might influence the risk of childhood ALL. In a total of 266 patients with childhood ALL and 266 healthy controls, genotypes of MEG3 rs7158663, rs3087918, rs11160608 and rs4081134 single nucleotide polymorphisms were investigated for their associations with childhood ALL. MEG3 rs7158663 AG and AA genotypes were significantly associated with ALL [odds ratio=1.61 (95% confidence interval=1.12-2.31) and 2.21 (1.16-4.22), respectively]. The A allele also exhibited a statistical association with higher risk of ALL (p=0.0015). There was no positive association as for rs3087918, rs11160608 or rs4081134. Interestingly, a significant interaction between MEG3 rs7158663 and age (≥3.5 years) and gender (male) was found. MEG3 rs7158663 AG/AA genotypes were associated with higher susceptibility to childhood ALL. These novel findings should be validated in larger populations and different ethnicities.

Long non-coding RNA MEG3 mediates the miR-149-3p/FOXP3 axis by reducing p53 ubiquitination to exert a suppressive effect on regulatory T cell differentiation and immune escape in esophageal cancer

BackgroundLong non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been implicated in the progression of esophageal cancer (EC). However, the specific mechanism of the involvement of MEG3 in EC development in relation to the regulation of immune escape remains uncertain. Thus, the aim of the current study was to investigate the effect of MEG3 on EC via microRNA-149-3p (miR-149-3p).MethodsGain- and loss-of-function experiments were initially performed in EC cells in addition to the establishment of a 4-nitroquinoline 1-oxide-induced EC mouse model aimed at evaluating the respective roles of forkhead box P3 (FOXP3), MEG3, miR-149-3p, mouse double minute 2 homolog (MDM2) and p53 in T cell differentiation and immune escape observed in EC.ResultsEC tissues were found to exhibit upregulated FOXP3 and MDM2 while MEG3, p53 and miR-149-3p were all downregulated. FOXP3 was confirmed to be a target gene of miR-149-3p with our data suggesting it reduced p53 ubiquitination and degradation by means of inhibiting MDM2. P53 was enriched in the promoter of miR-149-3p to upregulate miR-149-3p. The overexpression of MEG3, p53 or miR-149-3p or silencing FOXP3 was associated with a decline in CD25+FOXP3+CD4+ T cells, IL-10+CD4+ T cells and IL-4+CD4+ T cells in spleen tissues, IL-4, and IL-10 levels as well as C-myc, N-myc and Ki-67 expression in EC mice.ConclusionCollectively, MEG3 decreased FOXP3 expression and resulted in repressed regulatory T cell differentiation and immune escape in EC mice by upregulating miR-149-3p via MDM2-mediated p53.

MicroRNA-210/ Long non-coding RNA MEG3 axis inhibits trophoblast cell migration and invasion by suppressing EMT process

IntroductionPre-eclampsia is characterized by insufficient spiral artery remodeling, and trophoblast dysfunction plays an important role in this process. Noncoding RNAs (microRNAs (miRNAs) and long noncoding RNAs (LncRNAs) are included) can regulate trophoblasts. MicroRNA-210 (miR-210) can decrease trophoblast cell migration and invasion and may act as a biomarker for preeclampsia. LncRNA maternally expressed gene 3 (MEG3) plays a positive role in pre-eclampsia, and MEG3 can be a downstream target of miR-210 in human umbilical vein endothelial cells (HUVEC). However, the effect of miR-210 on MEG3 and the mechanism of action of the miR-210/MEG3 axis in trophoblasts remain unclear. MethodThe localization of miR-210 and MEG3 in the human placenta in early pregnancy was determined by in situ hybridization. Then, HTR8/SVneo cells were used to investigated the effect of miR-210 on MEG3 expression and biological activity of trophoblasts in the migration and invasion assays. Gain- and loss-of-function experiments were performed to determine the mechanism of action of miR-210 and MEG3 in Epithelial-mesenchymal transition (EMT) of HTR8/SVneo cells. ResultsThe qRT-PCR and western blotting results demonstrated that the upregulation of miR-210 decreases MEG3, N-cadherin and Vimentin expression and increases E-cadherin expression to inhibit EMT in HTR-8/SVneo cells. Inhibition of the expression of miR-210 results in the opposite effects. Gain- and loss-of-function assay indicated that miR-210 can impair the EMT, migration, and invasion of HTR8/SVneo cells by regulating the expression of MEG3. DisscussionMiR-210 may be a negative regulator of trophoblast EMT that acts by suppressing MEG3 expression.

Long Non-coding RNA MEG3 Promotes Renal Tubular Epithelial Cell Pyroptosis by Regulating the miR-18a-3p/GSDMD Pathway in Lipopolysaccharide-Induced Acute Kidney Injury.

Background and Objective: Acute kidney injury (AKI) is a complication of sepsis. Pyroptosis of gasdermin D (GSDMD)-mediated tubular epithelial cells (TECs) play important roles in pathogenesis of sepsis-associated AKI. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), an imprinted gene involved in tumorigenesis, is implicated in pyroptosis occurring in multiple organs. Herein, we investigated the role and mechanisms of MEG3 in regulation of TEC pyroptosis in lipopolysaccharide (LPS)-induced AKI.Materials and Methods: Male C57BL/6 mice and primary human TECs were treated with LPS for 24 h to establish the animal and cell models, respectively, of sepsis-induced AKI. Renal function was assessed by evaluation of serum creatinine and urea levels. Renal tubule injury score was assessed by Periodic acid-Schiff staining. Renal pyroptosis was assessed by evaluating expression of caspase-1, GSDMD, and inflammatory factors IL-1β and IL-18. Cellular pyroptosis was assessed by analyzing the release rate of LDH, expression of IL-1β, IL-18, caspase-1, and GSDMD, and using EtBr and EthD2 staining. MEG3 expression in renal tissues and cells was detected using RT-qPCR. The molecular mechanisms of MEG3 in LPS-induced AKI were assessed through bioinformatics analysis, RNA-binding protein immunoprecipitation, dual luciferase reporter gene assays, and a rescue experiment.Results: Pyroptosis was detected in both LPS-induced animal and cell models, and the expression of MEG3 in these models was significantly up-regulated. MEG3-knockdown TECs treated with LPS showed a decreased number of pyroptotic cells, down-regulated secretion of LDH, IL-1β, and IL-18, and decreased expression of GSDMD, compared with those of controls; however, there was no difference in the expression of caspase-1 between MEG3 knockdown cells and controls. Bioinformatics analysis screened out miR-18a-3P, and further experiments demonstrated that MEG3 controls GSDMD expression by acting as a ceRNA for miR-18a-3P to promote TECs pyroptosis.Conclusion: Our study demonstrates that lncRNA MEG3 promoted renal tubular epithelial pyroptosis by regulating the miR-18a-3p/GSDMD pathway in LPS-induced AKI.

The lncRNA MEG3/miR-16-5p/VGLL4 regulatory axis is involved in etoposide-induced senescence of tumor cells.

The senescence of tumor cells is an important tumor suppressor mechanism. The present study aimed to investigate the role of long non-coding RNA (lncRNA) MEG3 (maternally expressed gene 3) in the senescence process of tumor cells and its potential molecular mechanism by competitively binding with microRNA miR-16-5p to regulate the expression of VGLL4 (encoding vestigial like family member 4). We used etoposide to construct senescence models of tumor cells. The degree of cellular senescence was detected by senescence-associated β-galactosidase, cell cycle and senescence-associated secretory phenotype. The expression of lncRNA MEG3, miR-16-5p and VGLL4 in senescent or non-senescent cells was evaluated using a quantitative real-time reverse transcriptase-PCR (qRT-PCR) or western blotting. Dual luciferase reporter assays were used to detect the binding of miR-16-5p to lncRNA MEG3 and VGLL4. The mRNA and protein expression levels of senescence-related markers (p53, p21 and p16) were detected using qRT-PCR or western blotting. Compared to the control group, the expression of lncRNA MEG3 and VGLL4 was significantly up-regulated in senescent cells. Knockdown of lncRNA MEG3 and VGLL4 reduced the degree of senescence and the expression of p21 and p16. lncRNA MEG3 interfered with the expression of miR-16-5p in senescent A549 and MCF-7 cells. The expression of VGLL4 was regulated by miR-16-5p in senescent A549 and MCF-7 cells. lncRNA MEG3 participated in the senescent progress of tumor cells induced by etoposide via the miR-16-5p/VGLL4 axis. The present study has confirmed the regulatory role of the lncRNA MEG3/miR-16-5p/VGLL4 axis in the low-dose etoposide-induced tumor cell senescence model, which has potential clinical application with respect to treating malignant tumors.

Association of the Plasma Long Non-coding RNA MEG3 With Parkinson's Disease.

Objective: To investigate the expression level of the maternally expressed gene-3 (MEG3) of the free long non-coding RNA (lncRNAs) in the plasma of Parkinson's disease (PD) patients and its relationship with the disease.Methods: Thirty PD patients (PD group) who treated at Xuanwu Hospital of Capital University of Medical Sciences between January 2017 and December 2019 were selected as the research objects and 30 healthy subjects were enrolled in the study during the same period as the control group. Cognitive function was assessed according to the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function, Non-Motor Symptoms Scale (NMSS) was used to evaluate severity of non-motor symptoms. The relative expression of lncRNAs MEG3 in plasma was measured by PCR, and the levels of neuron-specific enolase (NSE), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in plasma were measured by ELISA, and the relationship with these all indexes was analyzed.Results: The NMSS score of PD group was significantly higher than that of the control group, while the MMSE and MoCA scores were significantly lower than that of the control group (P < 0.05); The relative expression of lncRNAs MEG3, NGF and BDNF levels of PD group were significantly lower than that of the control group, and NSE level was significantly higher than that of the control group (P < 0.05); The H&Y stage and NMSS score in PD group were negatively correlated with the relative expression of lncRNAs MEG3, the levels of NGF and BDNF (P < 0.05), and positively correlated with NSE (P < 0.05); The MMSE and MoCA scores in PD group were positively correlated with the relative expression of lncRNAs MEG3, NGF, BDNF levels (P < 0.05), and negatively correlated with NSE (P < 0.05); The relative expression of lncRNAs MEG3 in PD group was positively correlated with NGF, BDNF levels (P < 0.05), and negatively correlated with NSE (P < 0.05).Conclusion: The expression of lncRNAs MEG3 in the plasma of PD patients was downregulated compared to that of healthy control subjects, and its expression level was closely related to the aggravation of non-motor symptoms, cognitive decline, and PD stage. These associations may reflect the synergism of the increase of NSE and decrease of NGF and BDNF levels, highlighting plasma lncRNA MEG3 as a new candidate biomarker of PD.

Long Non-Coding RNA MEG3 Modifies Cell-Cycle, Migration, Invasion, and Proliferation Through AKAP12 by Sponging miR-29c in Meningioma Cells.

Meningioma (MEN) is a common central nervous system disease. Accumulating evidence indicated that long non-coding RNA maternally expressed gene 3 (MEG3) participated in the progression of MEN. However, the potential mechanisms of MEG3 in altering the aggressive phenotypes of MEN need further exploration. Levels of MEG3, microRNA (miR)-29c, and A-kinase anchor protein 12 (AKAP12) were determined using quantitative real-time Polymerase Chain Reaction (qRT-PCR) assay. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to verify the relationship between miR-29c and MEG3 or AKAP12. The protein level of AKAP12 was detected by western blot. Moreover, cell-cycle arrest, migration, invasion, and proliferation were assessed by flow cytometry, wound healing, transwell assays, and CCK-8 assay, respectively. Levels of MEG3 and AKAP12 were downregulated, while miR-29c was effectively increased in MEN tissues and cell line. Mechanically, MEG3 was a sponge of miR-29c to regulate the expression of AKAP12. Functionally, increase of MEG3 diminished cell-cycle, migration, invasion, and proliferation in MEN cells, and reintroduction of miR-29c could eliminate these effects. In addition, AKAP12 depletion overturned the inhibitory effects of miR-29c absence on cell-cycle, migration, invasion, and proliferation in vitro. Also, AKAP12 was co-regulated by MEG3/miR-29c axis. MEG3 mediated the aggressive behaviors of MEN cells via miR-29c/AKAP12 axis, supporting that MEG3 served as a promising biomarker for the diagnosis and treatment of human MEN.

RETRACTED: Long noncoding RNA MEG3 contributes to dysfunction of brain microvascular endothelial cells after intracerebral hemorrhage by regulating the miR-1930-5p/Mllt1 axis

Intracerebral hemorrhage (ICH) is a subtype of stroke and causes disability and death worldwide. The roles of long noncoding RNAs (lncRNAs) in brain function and neurological diseases have been revealed. LncRNA maternally expressed gene 3 (MEG3) is involved in neurological impairment, but its role in ICH remains unknown. The aim of this research is to explore the role of MEG3 in ICH. Here, we established an ICH mouse model via intracerebral injection of autologous blood. Primary brain microvascular endothelial cells (BMECs) were treated with oxygen-and-glucose-deprivation (OGD) plus hemin to establish the model in vitro. We observed that MEG3 expression was significantly upregulated in both ICH mouse model and OGD/hemin (OGD/H) induced BMECs. The downregulation of MEG3 suppressed cell apoptosis and the activation of NOD-like receptor family protein 3 (NLRP3) inflammasome in OGD/H-induced BMECs. In ICH mice, MEG3 downregulation inhibited cell apoptosis and improved brain dysfunction. Mechanistically, MEG3 was confirmed to act as a molecular sponge for microRNA (miR)-1930-5p, and Mllt1 was a downstream target for miR-1930-5p. MEG3 competitively bound with miR-1930-5p to upregulate Mllt1. We further verified that Mllt1 overexpression reversed the inhibitory effect of miR-1930-5p in OGD/H-induced BMECs. In conclusion, lncRNA MEG3 promoted the dysfunction of BMECs by modulating the miR-1930-5p/Mllt1 axis, which provides a potential target in gene therapy for brain injury following ICH.

Silencing of long non-coding RNA MEG3 alleviates lipopolysaccharide-induced acute lung injury by acting as a molecular sponge of microRNA-7b to modulate NLRP3

We aimed to elucidate the roles of the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3)/microRNA-7b (miR-7b)/NLR pyrin domain containing 3 (NLRP3) axis in lipopolysaccharide (LPS)-induced acute lung injury (ALI). Mouse alveolar macrophage NR8383 and mice were administrated with LPS to establish ALI models in vitro and in vivo. NLRP3 was silenced while miR-7b was overexpressed in LPS-induced NR8383 cell model of ALI. The interleukin-18 (IL-18) and IL-1β, as well as caspase-1, tumor necrosis factor-α (TNF-α) and IL-6 protein levels were assayed. To further investigate the underlying mechanisms of NLRP3 in ALI, lncRNA MEG3 was silenced and miR-7b was overexpressed in LPS-induced NR8383 cell model of ALI, after which in vivo experiments were performed for further verification. NLRP3 was highly expressed in LPS-induced NR8383 cell model of ALI. Silencing NLRP3 or overexpressing miR-7b inhibited IL-18 and IL-1β, as well as caspase-1, TNF-α and IL-6. LncRNA MEG3 could sponge miR-7b, and lncRNA MEG3 silencing or miR-7b overexpression downregulates NLRP3 expression, thus reducing IL-18 and IL-1β, as well as caspase-1, TNF-α and IL-6 levels. The in vivo experiments further confirmed the aforementioned findings. Silencing lncRNA MEG3 augments miR-7b binding to NLRP3 and downregulates NLRP3 expression, which ultimately improves LPS-induced ALI.

Long non-coding RNA MEG3 promotes cataractogenesis by upregulating TP53INP1 expression in age-related cataract

Age-related cataract (ARC) is the leading cause of visual impairment or even blindness among the aged population globally. Long non-coding RNA (LncRNA) has been proven to be the potential regulator of ARC. The latest study reveals that maternally expressed gene 3 (MEG3) promotes the apoptosis and inhibits the proliferation of multiple cancer cells. However, the expression and role of MEG3 in ARC are unclear. In this study, we investigated the effects of MEG3 in ARC and explored the regulatory mechanisms underlying these effects. We observed that MEG3 expression was up-regulated in the age-related cortical cataract (ARCC) lens capsules and positively correlated with the histological degree of ARCC. The pro-apoptosis protein, active caspase-3 and Bax increased in the anterior lens capsules of ARCC tissue, while the anti-apoptotic protein Bcl-2 decreased compared to normal lens. Knockdown of MEG3 increased the viability and inhibited the apoptosis of LECs upon the oxidative stress induced by H2O2. MEG3 was localized in both nucleus and cytoplasm in LECs. MEG3 facilitated TP53INP1 expression via acting as miR-223 sponge and promoting P53 expression. Additionally, TP53INP1 knockdown alleviated H2O2-induced lens turbidity. In summary, MEG3 promoted ARC progression by up-regulating TP53INP1 expression through suppressing miR-223 and promoting P53 expression, which would provide a novel insight into the pathogenesis of ARC.

Long Non-Coding RNA MEG3 Promotes Apoptosis of Vascular Cells and is Associated with Poor Prognosis in Ischemic Stroke.

Aim: This study focused on the expression pattern of long non-coding RNA maternally expressed gene 3 (MEG3) and its value in ischemic stroke (IS).Methods: The expression pattern and the roles of MEG3 in the development of IS were explored in mice IS model and human brain microvascular endothelial cells (hBMECs). A case-control study, including 215 IS patients and 153 controls, was also conducted to investigate its prognostic value.Results: In vivo study showed that MEG3 increased significantly in the IS group (P = 0.004), and its level remained stable within 3 to 48h after the onset of IS. Besides, the survival time of the mouse in the high MEG3 group was significantly lower than that in the low MEG3 group (P = 0.042). In vitro study showed that oxygen–glucose deprivation (OGD) treatment significantly up-regulated expressions of MEG3, Bax, and cleaved caspase-3, and further promoted apoptosis of hBMECs, while si-MEG3 blocked these effects. A human study showed that MEG3 increased markedly within 48h of IS onset and was positively associated with the National Institutes of Health Stroke Scale (r = 0.347, P < 0.001), modified Rankin Scale (r = 0.385, P < 0.001), high-sensitivity C-reactive protein (r = 0.221, P = 0.002) level, and infarct volume (r = 0.201, P = 0.006). Overall survival analysis showed that patients with higher MEG3 expression within 48h had a relatively poor prognosis (P < 0.001). Meanwhile, multivariate analysis revealed that MEG3 was an independent prognostic marker for unfavorable functional outcome and death in IS patients.Conclusions: This study suggested that MEG3 might be considered as an intervention point and potential prognostic indicator for IS.

Long non-coding RNA MEG3 is involved in osteogenic differentiation and bone diseases (Review).

Osteogenic differentiation originating from mesenchymal stem cells (MSCs) requires tight co-ordination of transcriptional factors, signaling pathways and biomechanical cues. Dysregulation of such reciprocal networks may influence the proliferation and apoptosis of MSCs and osteoblasts, thereby impairing bone metabolism and homeostasis. An increasing number of studies have shown that long non-coding (lnc)RNAs are involved in osteogenic differentiation and thus serve an important role in the initiation, development, and progression of bone diseases such as tumors, osteoarthritis and osteoporosis. It has been reported that the lncRNA, maternally expressed gene 3 (MEG3), regulates osteogenic differentiation of multiple MSCs and also acts as a critical mediator in the development of bone formation and associated diseases. In the present review, the proposed mechanisms underlying the roles of MEG3 in osteogenic differentiation and its potential effects on bone diseases are discussed. These discussions may help elucidate the roles of MEG3 in osteogenic differentiation and highlight potential biomarkers and therapeutic targets for the treatment of bone diseases.

Long Non-coding RNA MEG3 Activated by Vitamin D Suppresses Glycolysis in Colorectal Cancer via Promoting c-Myc Degradation.

Colorectal cancer (CRC), a common tumor, is characterized by a high mortality rate. Long non-coding RNA maternally expressed gene 3 (MEG3) serves a regulatory role in the carcinogenesis and progression of several types of cancer; however, its role in CRC remains largely unknown. The aim of this study was to explore the regulatory role and mechanism(s) of MEG3 in CRC. The Warburg effect or aerobic glycolysis is characteristic of the metabolism of tumor cells. To determine the effect of MEG3 on glycolysis of CRC cells, we used an XF analyzer to perform glycolysis stress test assays and found that overexpression of MEG3 significantly inhibited glycolysis, glycolytic capacity, as well as lactate production in CRC cells, whereas knockdown of MEG3 produced the opposite effect. Mechanistically, overexpression of MEG3 induced ubiquitin-dependent degradation of c-Myc and inhibited c-Myc target genes involved in the glycolysis pathway such as lactate dehydrogenase A, pyruvate kinase muscle 2, and hexokinase 2. Moreover, we found that MEG3 can be activated by vitamin D and vitamin D receptor (VDR). Clinical data demonstrated that MEG3 was positively associated with serum vitamin D concentrations in patients with CRC. We found that 1,25(OH)2D3 treatment increased MEG3 expression, and knockdown of VDR abolished the effect of MEG3 on glycolysis. These results indicate that vitamin D-activated MEG3 suppresses aerobic glycolysis in CRC cells via degradation of c-Myc. Thus, vitamin D may have therapeutic value in the treatment of CRC.

Long non-coding RNA MEG3 functions as a competing endogenous RNA of miR-93 to regulate bladder cancer progression via PI3K/AKT/mTOR pathway.

BackgroundMaternally expressed gene 3 (MEG3) is a long non-coding RNA (lncRNA) and involved in progression of various human tumors. However, its underlying regulatory mechanism in tumorigenesis of bladder cancer (BC) remains unclear. To demonstrate effects of MEG3 on BC cell proliferation and elaborate its regulatory mechanism in BC.MethodsAberrant expressions of MEG3 and miR-93-5p were induced by cell transfection. The mRNA and protein expression were analyzed using qRT-PCR and western blot. Cell proliferation was examined by CCK-8 assay and EdU staining. The targeted regulation effect of MEG3 on miR-93-5p was confirmed by luciferase reporter assay. The number of LC3 punctated cells was detected by immunofluorescence. Xeno-graft mouse model was constructed for in vivo validation.ResultsMEG3 was down-regulated with increased expression of miR-93-5p in BC cells and tissues. Luciferase reporter assay showed that miR-93-5p was a direct target of MEG3 and was negatively regulated by MEG3. MEG3 overexpression inhibited cell proliferation and the expression of proliferation-, apoptosis- and autophagy-related proteins. The activation of PI3K/AKT/mTOR pathway was also suppressed with elevated cell apoptosis. miR-93-5p overexpression counteracted these results. In vivo experiments, we confirmed that miR-93-5p overexpression reversed the MEG3 overexpression-mediated suppression on tumor growth and protein expression.ConclusionslncRNA MEG3 could function as a competing endogenous RNA of miR-93 to regulate the tumorigenesis of BC via PI3K/AKT/mTOR pathway. The present research provided a new perspective to understanding the pathogenic mechanism of BC, and an effective therapeutic target for BC.