Gene Summary

Gene:MEG3; maternally expressed 3
Aliases: GTL2, FP504, prebp1, PRO0518, PRO2160, LINC00023, NCRNA00023, onco-lncRNA-83
Summary:This gene is a maternally expressed imprinted gene. Multiple alternatively spliced transcript variants have been transcribed from this gene and all of them are long non-coding RNAs (lncRNAs). This gene is expressed in many normal tissues, but its expression is lost in multiple cancer cell lines of various tissue origins. It inhibits tumor cell proliferation in vitro. It also interacts with the tumor suppressor p53, and regulates p53 target gene expression. Its deletion enhances angiogenesis in vivo. Many experimental evidences demonstrate that this gene is a lncRNA tumor suppressor. [provided by RefSeq, Mar 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MEG3 (cancer-related)

Tokgun PE, Tokgun O, Kurt S, et al.
MYC-driven regulation of long non-coding RNA profiles in breast cancer cells.
Gene. 2019; 714:143955 [PubMed] Related Publications
AIM: MYC deregulation contributes to breast cancer development and progression. Deregulated expression levels of long non-coding RNAs (lncRNA) have been demonstrated to be critical players in development and/or maintenance of breast cancer. In this study we aimed to evaluate lncRNA expressions depending on MYC overexpression and knockdown in breast cancer cells.
MATERIALS AND METHODS: Cells were infected with lentiviral vectors by either knockdown or overexpression of c-MYC. LncRNA cDNA was transcribed from total RNA samples and lncRNAs were evaluated by qRT-PCR.
RESULTS: Our results indicated that some of the lncRNAs having tumor suppressor (GAS5, MEG3, lincRNA-p21) and oncogenic roles (HOTAIR) are regulated by c-MYC.
CONCLUSION: We observed that c-MYC regulates lncRNAs that have important roles on proliferation, cell cycle and etc. Further studies will give us a light to identify molecular mechanisms related to MYC-lncRNA regulatory pathways in breast cancer.

Luo Q, Cui M, Deng Q, Liu J
Comprehensive analysis of differentially expressed profiles and reconstruction of a competing endogenous RNA network in papillary renal cell carcinoma.
Mol Med Rep. 2019; 19(6):4685-4696 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs). ceRNA networks may serve important roles in various tumors, as demonstrated by an increasing number of studies; however, papillary renal cell carcinoma (PRCC)‑associated ceRNA networks mediated by lncRNAs remain unknown. Increased knowledge of ceRNA networks in PRCC may aid the identification of novel targets and biomarkers in the treatment of PRCC. In the present study, a comprehensive investigation of mRNA, lncRNA, and microRNA (miRNA) expression in PRCC was conducted using sequencing data from The Cancer Genome Atlas. Differential expression (DE) profiles of mRNAs, lncRNAs and miRNAs were evaluated, with 1,970 mRNAs, 1,201 lncRNAs and 96 miRNAs identified as genes with significantly different expression between PRCC and control paracancerous tissues. Based on the identified DEmRNAs, a protein‑protein interaction network was generated using the STRING database. Furthermore, a ceRNA network for PRCC was determined using a targeted assay combined with the DE of miRNAs, mRNAs and lncRNAs, enabling the identification of important lncRNA‑miRNA and miRNA‑mRNA pairs. Analysis of the ceRNA network led to the extraction of a subnetwork and the identification of lncRNA maternally expressed 3 (MEG3), lncRNA PWRN1, miRNA (miR)‑508, miR‑21 and miR519 as important genes. Reverse transcription‑quantitative polymerase chain reaction analysis was conducted to validate the results of the bioinformatics analyses; it was revealed that lncRNA MEG3 expression levels were downregulated in PRCC tumor tissues compared with adjacent non‑tumor tissues. In addition, survival analysis was conducted to investigate the association between identified genes and the prognosis of patients with PRCC, indicating the potential involvement of 13 mRNAs, 15 lncRNAs and six miRNAs. In conclusion, the present study may improve understanding of the regulatory mechanisms of ceRNA networks in PRCC and provide novel insight for future studies of prognostic biomarkers and potential therapeutic targets.

Mishra S, Verma SS, Rai V, et al.
Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases.
Cell Mol Life Sci. 2019; 76(10):1947-1966 [PubMed] Related Publications
The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.

Wang Y, Liang Z, Li H, et al.
NSPc1 polycomb protein complex binds and cross‑talks to lncRNAs in glioma H4 cells.
Oncol Rep. 2019; 41(4):2575-2584 [PubMed] Related Publications
Recently, emerging evidence shows that a number of long non‑coding RNAs (lncRNAs) recruit polycomb group (PcG) proteins to specific chromatin loci to silence relevant gene expression. In the present study, we provided evidence that lncRNA candidates, selected by bioinformatic analysis and nervous system polycomb 1 (NSPc1), a key polycomb repressive complex 1 (PRC1) member, were highly expressed in glioma H4 cells in contrast to that noted in non‑cancerous cells. RNA binding protein immunoprecipitation (RIP) assays demonstrated that metastasis associated lung adenocarcinoma transcript 1 (MALAT1), SOX2 overlapping transcript (SOX2OT) and maternally expressed 3 (MEG3) among the 8 candidates bound to the NSPc1 protein complex in glioma H4 cells. Furthermore, overexpression of NSPc1 caused a decrease in the expression of MALAT1 and MEG3 and increased expression of SOX2OT, while NSPc1 downregulation caused the levels of all three genes to increase. Meanwhile, suppression of the expression of MALAT1 increased the expression levels of mRNA and protein of NSPc1, whereas downregulation of the expression of SOX2OT decreased NSPc1 expression. Moreover, a significant decrease in cell growth and increased cell apoptosis were observed in the transfected H4 cells by MTT assay and flow cytometric analysis. The results showed that the reduced co‑expression between NSPc1 and MALAT1/SOX2OT decreased the proliferation and promoted the death of H4 cells more obviously than the respectively decrease in expression of NSPc1, MALAT1 and SOX2OT. Remarkably, the influence of a simultaneously decreased expression of NSPc1 and SOX2OT on promoting cell apoptosis was more obvious than the total effect of the separate downregulation of NSPc1 and SOX2OT on accelerating cell death. However, that impact was partially counteracted in the silencing of the co‑expression of MALAT1 and NSPc1. Furthermore, they cooperated to affect transcription of p21 and OCT4.Briefly, these data suggest NSPc1 polycomb protein complex binding and cross‑talk to lncRNAs in glioma H4 cells, offering new insight into the important function of polycomb protein complex and lncRNA interactions in glioma cells and provide a novel view of potential biomarkers and targets for the diagnosis and therapy of glioma.

Dai Y, Wan Y, Qiu M, et al.
lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway.
Cell Physiol Biochem. 2018; 51(6):2872-2886 [PubMed] Related Publications
BACKGROUND/AIMS: Dysregulation of long noncoding RNAs (lncRNAs) is associated with the proliferation and metastasis in a variety of cancers, of which lncRNA maternally expressed gene 3 (MEG3) has been indicated as a tumor suppressor in multiple malignancies. However, the underlying mechanisms by which MEG3 contributes to human hemangiomas (HAs) remain undetermined.
METHODS: qRT-PCR analysis was performed to examine the expression levels of MEG3 and VEGF in proliferating or involuting phase HAs. MTT, colony formation assay, flow cytometry analysis and a subcutaneous xenograft tumor model were conducted to assess the effects of MEG3 on the HAs tumorigenesis. The interaction between MEG3 and miRNAs or their downstream pathways was evidenced by bioinformatic analysis, luciferase report assays, RNA immunoprecipitation (RIP) assay. and Western blot analysis.
RESULTS: The expression of MEG3 was substantially decreased and had a negative correlation with VEGF expression in proliferating phase HAs, as compared with the involuting phase HAs and normal skin tissues. Ectopic expression of MEG3 suppressed cell proliferation, colony formation and induced cycle arrest in vitro and in vivo, followed by the downregulation of VEGF and cyclinD1, but knockdown of MEG3 reversed these effects. Furthermore, MEG3 was verified to act as a sponge of miR-494 in HAs cells, and miR-494 counteracted MEG3-caused anti-proliferative effects by regulating PTEN/PI3K/AKT pathway, and exhibited the negative correlation with MEG3 and PTEN expression in proliferating phase HAs.
CONCLUSION: Our findings suggested that lncRNA MEG3 inhibited HAs tumorigenesis by sponging miR-494 and regulating PTEN/PI3K/AKT pathway.

Shihabudeen Haider Ali MS, Cheng X, Moran M, et al.
LncRNA Meg3 protects endothelial function by regulating the DNA damage response.
Nucleic Acids Res. 2019; 47(3):1505-1522 [PubMed] Free Access to Full Article Related Publications
The role of long non-coding RNAs (lncRNAs) in regulating endothelial function through the DNA damage response (DDR) remains poorly understood. In this study, we demonstrate that lncRNA maternally expressed gene 3 (Meg3) interacts with the RNA binding protein polypyrimidine tract binding protein 3 (PTBP3) to regulate gene expression and endothelial function through p53 signaling ─ a major coordinator of apoptosis and cell proliferation triggered by the DDR. Meg3 expression is induced in endothelial cells (ECs) upon p53 activation. Meg3 silencing induces DNA damage, activates p53 signaling, increases the expression of p53 target genes, promotes EC apoptosis, and inhibits EC proliferation. Mechanistically, Meg3 silencing reduces the interaction of p53 with Mdm2, induces p53 expression, and promotes the association of p53 with the promoters of a subset of p53 target genes. PTBP3 silencing recapitulates the effects of Meg3 deficiency on the expression of p53 target genes, EC apoptosis and proliferation. The Meg3-dependent association of PTBP3 with the promoters of p53 target genes suggests that Meg3 and PTBP3 restrain p53 activation. Our studies reveal a novel role of Meg3 and PTBP3 in regulating p53 signaling and endothelial function, which may serve as novel targets for therapies to restore endothelial homeostasis.

Ghaedi H, Mozaffari MAN, Salehi Z, et al.
Co-expression profiling of plasma miRNAs and long noncoding RNAs in gastric cancer patients.
Gene. 2019; 687:135-142 [PubMed] Related Publications
PURPOSE: The recent researches indicate that differential non-coding RNAs expression signatures could be associated with the pathogenesis of gastric cancer (GC). However, there are few studies focused on lncRNA-miRNAs co-expression profiling in GC patients. Therefore, in the present study the expression of H19 and MEG3 and their related miRNAs including miR-148a-3p, miR-181a-5p, miR-675-5p and miR-141-3p were determined in the plasma samples of GC patients and controls.
MATERIALS AND METHODS: This case-control study included 62 GC patients and 40 age- sex matched controls. The non-coding RNA levels were assessed by real-time PCR. Further, using in silico analysis, we identified shared targets of studied miRNAs and performed GC-associated pathway enrichment analysis.
RESULTS: Our results showed that the H19 level was significantly (P = 0.008) elevated and MEG3 expression was significantly (P = 0.002) down-regulated in GC patients compared to healthy participants. Furthermore, it was revealed that the miR-675-5p level was increased, while miR-141-3p plasma levels were significantly reduced in GC patients (P < 0.05). We did not observe a significant difference for miR-148a-3p (P = 0.682) and miR-181a-5p (P = 0.098) expression between groups. In addition, the expression levels of H19, MEG3 and miR-148a-3p were associated with some clinicopathological features of patients (P < 0.05). ROC analysis revealed that a combination of H19, MEG3 and miR-675-5p levels able to discriminate controls and GC subjects with 88.87% sensitivity and 85% specificity (AUC, 0.927; 0.85-0.96 CI, P < 0.0001).
CONCLUSION: The results of current study demonstrated that combination of H19, MEG3 and miR-675-5p expression levels could provide a potential diagnostic panel for GC.

Bruno C, Blagoskonov O, Barberet J, et al.
Sperm imprinting integrity in seminoma patients?
Clin Epigenetics. 2018; 10(1):125 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Testicular germ cell tumor such as seminoma is strongly associated with male reproductive problems commonly associated with the alteration of sperm parameters as described in testicular dysgenesis syndrome. Interestingly, numerous studies have reported that the precursor of germ cell cancer, germ cell neoplasia in situ (GCNIS), present similarities to fetal gonocytes, specifically characterized by global DNA hypomethylation particularly on imprinting sequences. These disorders may have a common origin derived from perturbations of embryonal programming during fetal development. Presently, there is no available information concerning the sperm DNA methylation patterns of testicular cancer patients. For the first time, we evaluated the sperm imprinting of seminoma patients. A total of 92 cryopreserved sperm samples were included, 31 before seminoma treatment (S): 23 normozoospermic (SN) and 8 oligozoospermic (SO) and 61 sperm controls samples: 31 normozoospermic (N) and 30 oligozoospermic (O). DNA methylation levels of seven differentially methylated regions (DMRs) of imprinted genes [H19/IGF2: IG-DMR (CTCF3 and CTCF6 of H19 gene); IGF2-DMRs (DMR0 and DMR2); MEG3/DLK1:IG-DMR; SNURF:TSS-DMR; KCNQ1OT1:TSS-DMR] were assessed by pyrosequencing. All comparative analyses were adjusted for age.
RESULTS: Comparisons of sperm DNA methylation levels between seminoma (S) and normozoospermic (N) samples showed a significant difference for the SNURF sequence (p = 0.017), but after taking into account the sperm parameters, no difference was observed. However, we confirmed a significant association between oligozoospermia (O) and imprinting defects for H19/IGF2-CTCF6 (p = 0.001), MEG3/DLK1 (p = 0.017), IGF2-DMR2 (p = 0.022), and SNURF (p = 0.032) in comparison with control groups (N).
CONCLUSIONS: This study highlights the high risk of sperm imprinting defects in cases of oligozoospermia and shows for the first time that seminoma patients with normal spermatogenesis present sperm imprinting integrity. These data suggest a low probability of the involvement of a common imprinting defect in fetal cells leading to both TGCT and subfertility.

Wang J, Xu W, He Y, et al.
LncRNA MEG3 impacts proliferation, invasion, and migration of ovarian cancer cells through regulating PTEN.
Inflamm Res. 2018; 67(11-12):927-936 [PubMed] Related Publications
OBJECTIVE AND DESIGN: We investigated the expressions of lncRNA MEG3 and PTEN in ovarian cancer tissues and their effects on cell proliferation, cycle and apoptosis of ovarian cancer.
METHODS: Expression levels of MEG3 in ovarian cancer cell lines and normal ovarian cell lines were detected by qRT-PCR. Cell viability was detected by MTT assay. Cell apoptosis and cell cycle distribution were measured by flow cytometry. Cell invasion capability was tested by transwell assay. Cell migration capacity was tested by wound healing. The xenograft model was constructed to explore the effect of lncRNA MEG3 on ovarian cancer in vivo.
RESULT: Compared with normal ovarian cells, expression levels of MEG3 and PTEN were relatively lower in ovarian cancer cells. There was a positive correlation between the expression of PTEN and the expression of MEG3. Enhanced expression level of PTEN suppressed SKOV3 cell proliferation, increased cell apoptosis rate, and decreased cell invasion and migration.
CONCLUSION: LncRNA MEG3 and PTEN were down-regulated in ovarian cancer cells. LncRNA MEG3 regulated the downstream gene PTEN in ovarian cancer cells to prohibit cell proliferation, promote apoptosis and block cell cycle progression.

Zhao H, Wang X, Feng X, et al.
Long non-coding RNA MEG3 regulates proliferation, apoptosis, and autophagy and is associated with prognosis in glioma.
J Neurooncol. 2018; 140(2):281-288 [PubMed] Related Publications
PURPOSE: Accumulating evidence indicates that dysregulated long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis and cancer progression. LncRNA-maternally expressed gene 3 (MEG3) has been shown to be involved in the initiation and development of several cancers, including glioma. However, the clinical prognostic value of MEG3 in glioma has not yet been fully elucidated.
METHODS: The expression levels of MEG3 were detected in 79 glioma tissues and adjacent normal brain tissues, as well as, glioma cells and normal human astrocytes by qRT-PCR. Kaplan-Meier and Cox regression methods were utilized for the survival analysis. MTT assay, flow cytometry, and immunofluorescence assay were carried out to detect the impact of MEG3 on glioma cell proliferation, apoptosis, and autophagy.
RESULT: The current results showed that MEG3 expression was significantly downregulated in glioma tissues and cell line and negatively correlated with WHO grade in glioma patients. Low MEG3 expression was significantly associated with the advanced WHO grade, low Karnofsky performance score (KPS), IDH wild-type, and tumor recurrence. Patients displaying a low expression of MEG3 contributed to poor overall survival. The downregulated level of MEG3, advanced WHO grade, low KPS, IDH wild-type, and tumor recurrence were independent poor prognostic indicators in glioma patients. The in vitro experiments demonstrated that the MEG3 overexpression remarkably suppressed the proliferation while facilitating apoptosis and autophagy in glioma cells.
CONCLUSIONS: These findings indicated a critical role of MEG3 in glioma cell proliferation, apoptosis, and autophagy. Also, the gene was found to be significantly associated with the prognosis in glioma patients. Thus, it might provide a new target for predicting prognosis and therapeutic intervention in glioma.

Cui X, Yi Q, Jing X, et al.
Mining Prognostic Significance of MEG3 in Human Breast Cancer Using Bioinformatics Analysis.
Cell Physiol Biochem. 2018; 50(1):41-51 [PubMed] Related Publications
BACKGROUND/AIMS: Maternally expressed gene 3 (MEG3) is an imprinted gene with maternal expression, which may function as a tumor suppressor by inhibiting angiogenesis. To identify the prognostic value of MEG3 in breast cancer, systematic analysis was performed in this study.
METHODS: To evaluate gene alteration during breast carcinogenesis, we explored MEG3 expression using the Serial Analysis of Gene Expression Genie suite and Oncomine analysis. The prognostic roles of MEG3 in breast cancer were investigated using the PrognoScan database. The heat map and methylation status of MEG3 were determined using the UCSC Genome Browser.
RESULTS: We found that MEG3 was more frequently downregulated in breast cancer than in normal tissues and this correlated with prognosis. However, estrogen receptor and progesterone receptor status were found to be positively correlated with MEG3 expression. Conversely, basal-like status, triple-negative breast cancer status, and Scarff Bloom & Richardson grade criterion were negatively correlated with MEG3 expression. Following data mining in multiple big data databases, we confirmed a positive correlation between MEG3 and heparan sulfate proteoglycan 2 (HSPG2) expression in breast cancer tissues.
CONCLUSION: MEG3 could be adopted as a marker to predict the prognosis of breast cancer with HSPG2. However, large-scale and comprehensive research is needed to clarify our results.

Terashima M, Ishimura A, Wanna-Udom S, Suzuki T
J Biol Chem. 2018; 293(47):18016-18030 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
Long noncoding RNAs (lncRNAs) are important regulatory molecules in various biological and pathological processes, including cancer development. We have previously shown that the

Zhang L, Yu S, Wang C, et al.
Establishment of a non‑coding RNAomics screening platform for the regulation of KRAS in pancreatic cancer by RNA sequencing.
Int J Oncol. 2018; 53(6):2659-2670 [PubMed] Related Publications
KRAS oncogene point mutations occur in >95% of patients with pancreatic cancer. The KRAS protein can activate various downstream effector molecules that affect proliferation and differentiation. MS2 binding sites (MS2bs) are RNAs of 19 bp in length that can bind MS2 coat proteins with their specific stem-loop structure. The MS2 binding site sequence of the 19-nucleotide stem-loop is ACATGAGGATCACCCATGT. We constructed an expression vector that expresses the KRAS non‑coding region coupled with 12 copies of MS2bs in series and established a high-throughput library for collecting microRNA (miRNA or miR)- and long non‑coding RNA (lncRNA)-omics that regulate KRAS. To the best of our knowledge, this is the first study to combine RNA-protein interactions with RNA sequencing to obtain KRAS-associated non‑coding RNAs. As a result, we identified several miRNA precursors that belong to the let-7 and miR-34, -30 and -143 families, as well as relevant lncRNAs and their families (MALAT1, MEG3_2 and TUG1_1-4). Our databank of non‑coding RNAs (mainly miRNAs and lncRNAs) that regulate KRAS is expected to greatly enhance our understanding of KRAS regulation-associated tumorigenesis and may aid in the development of gene therapies for pancreatic cancer.

Xu J, Su C, Zhao F, et al.
Paclitaxel promotes lung cancer cell apoptosis via MEG3-P53 pathway activation.
Biochem Biophys Res Commun. 2018; 504(1):123-128 [PubMed] Related Publications
Paclitaxel (PTX) is a first-line chemotherapy drug for advanced non-small cell lung cancer (NSCLC). The long-chain non-coding RNA maternally expressed gene 3 (MEG3) is a recognized tumor suppressor. This study aimed to explore the effects of PTX on the expression of MEG3 and its anti-tumor mechanism in lung cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were performed to determine cell proliferation. Quantitative polymerase chain reaction was used to determine the levels of MEG3 expressions. Western blot and immunofluorescence were used to detect protein levels. Small interfering RNA or pCDNA-MEG3 transfection was used to downregulate or upregulate MEG3 expression. Dichlorof luorescein diacetate was used to detect intracellular reactive oxygen species. Flow cytometry was used to analyze apoptosis. PTX significantly inhibited the proliferation of NSCLC cells and increased the expressions of MEG3 and P53. The downregulation of MEG3 attenuated PTX-induced cytotoxicity, whereas upregulation of MEG3 induced cell death and increased P53 expression. The inhibition of P53 caused no effect on the upstream MEG3 expression. Our results suggest that the MEG3-P53 pathway is involved in the apoptosis of A549 cells induced by PTX.

Shen X, Bai H, Zhu H, et al.
Long Non-Coding RNA MEG3 Functions as a Competing Endogenous RNA to Regulate HOXA11 Expression by Sponging miR-181a in Multiple Myeloma.
Cell Physiol Biochem. 2018; 49(1):87-100 [PubMed] Related Publications
BACKGROUND/AIMS: Long non-coding RNA maternally expressed gene 3 (MEG3) has been reported to play an essential role in cancer progression and metastasis. However, the overall biological role and regulatory mechanism of MEG3 in multiple myeloma (MM) development and progression remains largely ill-defined.
METHODS: MEG3 and miR-181a expression of MM patients were analyzed by publicly available MM data sets. Cell counting kit-8 and flow cytometry analysis were used to identify the function of MEG3 on MM in vitro. Additionally, we conducted tumor formation experiments in mice models to explain the role of MEG3 on MM in vivo. Then, several mechanism experiments, including dual-luciferase reporter assay and RNA immunoprecipitation were performed to evaluate the emulative relationship between MEG3 and miR-181a.
RESULTS: In this research, we found that MEG3 was downregulated in MM patients, which was linked with tumor progression. In addition, we demonstrated that miR-181a was overexpressed in MM patients in consistent with its cancer-promoting function. Importantly, several mechanism experiments revealed that MEG3, acting as an endogenous competitive RNA, could contend with miR-181a to inhibit tumor progression. Furthermore, as the target mRNA of miR-181a, homeobox gene A11(HOXA11) could be positively regulated by MEG3 through sponging miR-181a competitively in vitro.
CONCLUSION: Our present work supplies the first discovery of a MEG3/miR-181a/HOXA11 regulatory network in MM and highlights that MEG3 may serve as a promising target for MM therapy in the future.

Wang H, Li H, Zhang L, Yang D
Overexpression of MEG3 sensitizes colorectal cancer cells to oxaliplatin through regulation of miR-141/PDCD4 axis.
Biomed Pharmacother. 2018; 106:1607-1615 [PubMed] Related Publications
The existence of drug resistance is the main reason for chemotherapeutic failure in malignancies. Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) is implicated with tumorigenesis and chemoresistance. In the present study, we aimed to identify the role of MEG3 in oxaliplatin-resistant colorectal cancer (CRC) and its potential mechanisms. MEG3 was down-regulated in oxaliplatin-resistant CRC tissues and cell lines. Low MEG3 expression was correlated with poor prognosis of CRC patients. Overexpression of MEG3 improved oxaliplatin sensitivity of HT29/OXA and HCT116/OXA cells. MEG3 suppressed miR-141 expression in HCT116/OXA cells. Moreover, MEG3 elevated PDCD4 expression through targeting miR-141, acting as a competing endogenous RNA (ceRNA). miR-141 inhibition or PDCD4 up-regulation could mimic the functional role in oxaliplatin resistance, which was counteracted by overexpression of MEG3. Collectively, MEG3 facilitated the sensitivity of CRC cells to oxaliplatin by regulating miR-141/PDCD4 axis, providing a novel therapeutic strategy for CRC.

Yang Z, Li H, Li J, et al.
Association Between Long Noncoding RNA MEG3 Polymorphisms and Lung Cancer Susceptibility in Chinese Northeast Population.
DNA Cell Biol. 2018; 37(10):812-820 [PubMed] Related Publications
Long noncoding RNA (lncRNA) maternal-expressed gene 3 (MEG3) is associated with proliferation of various tumor cells and has decreased expression in many types of cancers. In this study, we aimed at demonstrating the association between MEG3 polymorphisms and the risk of lung cancer in northeast China. There were 526 lung cancer patients and 526 healthy controls included in this hospital-based case-control study. The genotyping of two polymorphisms, rs7158663 G > A and rs4081134 G>A, was performed by the Taqman allelic discrimination method. We found that MEG3 rs4081134-AA may be associated with the risk of lung cancer (AA vs. GG: adjusted odds ratio [OR] = 0.487, confidence interval [95% CI] = 0.257-0.897, p = 0.030; AA vs. AG+GG: adjusted OR = 0.522, 95% CI = 0.274-0.992, p = 0.047). Similar associations in several subgroups were found in subsequent stratified analysis. Further, there were no statistically significant interactions of rs4081134 polymorphism and smoking to lung cancer susceptibility. In addition, the associations between the MEG3 rs7158663 polymorphism and lung cancer susceptibility were not found. These results indicate that the MEG3 rs4081134 polymorphism was significantly associated with lung cancer susceptibility in the Chinese population.

Sherpa C, Rausch JW, Le Grice SF
Structural characterization of maternally expressed gene 3 RNA reveals conserved motifs and potential sites of interaction with polycomb repressive complex 2.
Nucleic Acids Res. 2018; 46(19):10432-10447 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
Long non-coding RNAs (lncRNAs) have emerged as key players in gene regulation. However, our incomplete understanding of the structure of lncRNAs has hindered molecular characterization of their function. Maternally expressed gene 3 (Meg3) lncRNA is a tumor suppressor that is downregulated in various types of cancer. Mechanistic studies have reported a role for Meg3 in epigenetic regulation by interacting with chromatin-modifying complexes such as the polycomb repressive complex 2 (PRC2), guiding them to genomic sites via DNA-RNA triplex formation. Resolving the structure of Meg3 RNA and characterizing its interactions with cellular binding partners will deepen our understanding of tumorigenesis and provide a framework for RNA-based anti-cancer therapies. Herein, we characterize the architectural landscape of Meg3 RNA and its interactions with PRC2 from a functional standpoint.

Zhang Z, Wang S, Liu W
EMT-related long non-coding RNA in hepatocellular carcinoma: A study with TCGA database.
Biochem Biophys Res Commun. 2018; 503(3):1530-1536 [PubMed] Related Publications
Accumulating evidence suggest that dysregulated expression of long non-coding RNA (lncRNA) plays a critical role in human tumorigenesis. However, little is known about the lncRNA implicated in the epithelial-to-mesenchymal transition (EMT) process. In this study, we performed data mining in The Cancer Genome Atlas (TCGA) hepatocellular carcinoma (HCC) data set and identified the a spectrum of differentially expressed lncRNAs implicated the EMT process of HCC, and functionally validated their roles in LM3 cells. Especially, lncRNA WDFY3-AS2-, LINC00472-, MIAT-, and MEG3-associated genes were significantly enriched in EMT-linked pathways. Loss-of-function study showed that genetic silencing of WDFY3-AS3, MIAT, and MEG3, but not LINC00472, resulted in reduced N-cadherin expression, cell migration, and cell invasion. Collectively, our results identify several lncRNAs that regulate the EMT process of HCC, which provides critical information for HCC tumorigenesis and potential therapeutic targets.

Liu Y, Yue P, Zhou T, et al.
LncRNA MEG3 enhances
Biomed Pharmacother. 2018; 105:1232-1239 [PubMed] Related Publications
BACKGROUND: Long non-coding RNA (LncRNA) MEG3 has been demonstrated as a tumor suppressor in various cancers, including thyroid carcinoma (TC). However, the detail functions and possible mechanisms of MEG3 in
METHODS: qRT-PCR was performed for the detection of MEG3 and miR-182 levels.
RESULTS: MEG3 expression was down-regulated in TC tumor tissues, and the cumulative survival rate was decreased in low MEG3 expression group in TC patients under
CONCLUSIONS: MEG3 enhanced the radiosensitivity of

Sellers ZP, Schneider G, Maj M, Ratajczak MZ
Analysis of the Paternally-Imprinted DLK1-MEG3 and IGF2-H19 Tandem Gene Loci in NT2 Embryonal Carcinoma Cells Identifies DLK1 as a Potential Therapeutic Target.
Stem Cell Rev Rep. 2018; 14(6):823-836 [PubMed] Related Publications
The paternally-imprinted genes insulin-like growth factor 2 (IGF2), H19, delta-like homologue 1 (DLK1), and maternally-expressed gene 3 (MEG3) are expressed from the tandem gene loci IGF2-H19 and DLK1-MEG3, which play crucial roles in initiating embryogenesis and development. The erasure of imprinting (EOI) at differentially methylated regions (DMRs) which regulate the expression of these genes maintains the developmental quiescence of primordial germ cells (PGCs) migrating through the embryo proper during embryogenesis and prevents them from forming teratomas. To address the potential involvement of the IGF2-H19 and DLK1-MEG3 loci in the pathogenesis of embryonal carcinoma (EC), we investigated their genomic imprinting at DMRs in the human PGC-derived EC cell line NTera-2 (NT2). We observed EOI at the IGF2-H19 locus and, somewhat to our surprise, a loss of imprinting (LOI) at the DLK1-MEG3 locus. As a result, NT2 cells express imprinted gene ratios from these loci such that there are i) low levels of the proliferation-promoting IGF2 relative to ii) high levels of the proliferation-inhibiting long noncoding RNA (lncRNA) H19 and iii) high levels of proliferation-promoting DLK1 relative to iv) low levels of the proliferation-inhibiting lncRNA MEG3. Consistent with this pattern of expression, the knockdown of DLK1 mRNA by shRNA resulted in decreased in vitro cell proliferation and in vivo tumor growth as well as decreased in vivo organ seeding by NT2 cells. Furthermore, treatment of NT2 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-azaD) inhibited their proliferation. This inhibition was accompanied by changes in expression of both tandem gene sets: a decrease in the expression of DLK1 and upregulation of the proliferation-inhibiting lncRNA MEG3, and at the same time upregulation of IGF2 and downregulation of the lncRNA H19. These results suggest that the DLK1-MEG3 locus, and not the IGF2-H19 locus, drives the tumorigenicity of NT2 cells. Based on these results, we identified DLK1 as a novel treatment target for EC that could be downregulated by 5-azaD.

Feng SQ, Zhang XY, Fan HT, et al.
Up-regulation of LncRNA MEG3 inhibits cell migration and invasion and enhances cisplatin chemosensitivity in bladder cancer cells.
Neoplasma. 2018; 65(6):925-932 [PubMed] Related Publications
It has been proven that maternally expressed 3 (MEG3), a long non-coding RNA (LncRNA), is down-regulated and inversely correlated with prognosis in various types of cancer, including bladder cancer (BC). Nevertheless, the role of MEG3 in BC has not been fully identified. Herein, we found that MEG3 expression was reduced in 21 BC tumor tissue samples compared to corresponding adjacent tissues. We then established T24 and 5637 cells with a stably integrated expression of MEG3 by G418 resistance screening, and data revealed that the BC cells over-expressing MEG3 displayed weaker migration and invasion ability than control cells. The expression and activity of matrix metalloproteinase (MMP)2 and MMP9 were down-regulated when MEG3 was over-expressed. Moreover, MEG3 over-expression sensitized BC cells to the chemotherapy drug cisplatin (DDP). DDP treatment significantly induced cell apoptosis, down-regulated bcl2 expression, and up-regulated cleaved-caspase-3 and bax expression in BC cells with MEG3 over-expression. MEG3 and p53 can also stimulate mutual expression in BC cells, thus indicating a potential positive feedback loop of MEG3 and p53. Our combined results suggest that over-expression of MEG3 inhibits migration and invasion and enhances DDP chemo-sensitivity in bladder cancer cells.

Kumar A, Nayak S, Pathak P, et al.
Identification of miR-379/miR-656 (C14MC) cluster downregulation and associated epigenetic and transcription regulatory mechanism in oligodendrogliomas.
J Neurooncol. 2018; 139(1):23-31 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
INTRODUCTION: Although role of individual microRNAs (miRNAs) in the pathogenesis of gliomas has been well studied, their role as a clustered remains unexplored in gliomas.
METHODS: In this study, we performed the expression analysis of miR-379/miR-656 miRNA-cluster (C14MC) in oligodendrogliomas (ODGs) and also investigated the mechanism underlying modulation of this cluster.
RESULTS: We identified significant downregulation of majority of the miRNAs from this cluster in ODGs. Further data from The Cancer Genome Atlas (TCGA) also confirmed the global downregulation of C14MC. Furthermore, we observed that its regulation is maintained by transcription factor MEF2. In addition, epigenetic machinery involving DNA and histone-methylation are also involved in its regulation, which is acting independently or in synergy. The post- transcriptionally regulatory network of this cluster showed enrichment of key cancer-related biological processes such as cell adhesion and migration. Also, there was enrichment of several cancer related pathways viz PIK3 signaling pathway and glioma pathways. Survival analysis demonstrated association of C14MC (miR-487b and miR-409-3p) with poor progression free survival in ODGs.
CONCLUSION: Our work demonstrates tumor-suppressive role of C14MC and its role in pathogenesis of ODGs and therefore could be relevant for the development of new therapeutic strategies.

Cui HB, Ge HE, Wang YS, Bai XY
MiR-208a enhances cell proliferation and invasion of gastric cancer by targeting SFRP1 and negatively regulating MEG3.
Int J Biochem Cell Biol. 2018; 102:31-39 [PubMed] Related Publications
The present studies have identified that microRNAs function as regulators in different diseases including cancers. However, the expression patterns and underlying molecular mechanisms of miR-208a involved in gastric cancer (GC) remain little known. In the study, our results demonstrated that miR-208a expression was significantly increased in GC tissues compared with adjacent normal tissues by performing qRT-PCR. Higher miR-208a expression was association with lymph node metastasis and TNM stage in GC patients. Kaplan-Meier analysis verified that patients with higher miR-208a expression were significantly associated with shorter overall survival (OS) time. Univariate and multivariate Cox analysis revealed that lymph node metastasis, TNM stage and higher miR-208a were independent risks factors of OS time. Ectopic expression of miR-208a by treatment with miR-208a mimic promoted cell proliferation and invasion abilities, but downregulation of miR-208a by treatment with miR-208a inhibitor had an opposite effects. Furthermore, we identified specific targeting sites for miR-208a in the 3'-untranslated region (3'-UTR) of the SFRP1 gene by dual-luciferase reporter assay. Upregulation of MiR-208a promoted cell proliferation and invasion by suppressing SFRP1 expression in GC cells. Moreover, dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and qRT-PCR analysis demonstrated that miR-208a targeted MEG3 and negatively regulated MEG3 expression in GC cells. Thus, these data indicated that miR-208a promoted GC progression by targeting SFRP1 and negatively regulating MEG3, which may be a potential therapeutic target of GC.

Li Z, Yang L, Liu X, et al.
Long noncoding RNA MEG3 inhibits proliferation of chronic myeloid leukemia cells by sponging microRNA21.
Biomed Pharmacother. 2018; 104:181-192 [PubMed] Related Publications
The long noncoding RNA (lnc) maternally expressed 3 (MEG3) is downregulated in many types of cancers. However, the relationship between lncRNA MEG3, microRNA-21 (miR-21) and chronic myeloid leukemia (CML) blast crisis is unknown. This study examined bone marrow samples from 40 CML patients and 10 healthy donors. Proliferation and apoptosis assays, real-time polymerase chain reaction (PCR), bisulfite sequencing PCR, Western blotting, luciferase assay, RNA pull-down, RNA immunoprecipitation (RIP), co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP) were performed. We found that MEG3 and PTEN expression were down-regulated, whereas, MDM2, DNMT1 and miR-21 were up-regulated in the accelerated and blast phases of CML. Treated with 5-azacytidine decreased the level of MDM2, DNMT1 and miR21, but increased the level of MEG3 and PTEN. Overexpression of MEG3 and silencing the expression of miR-21 inhibited proliferation and induced apoptosis. MEG3 overexpression and silencing the expression of miR21 influence the levels of MMP-2, MMP-9, bcl-2 and Bax. MEG3 was able to interact with MDM2 and EZH2. MDM2 could interact with DNMT1 and PTEN. MYC and AKT can interact with EZH2. ChIP-seq showed that the promoter of KLF4 and SFRP2 interacts with DNMT1. In conclusion, lncRNA MEG3 and its target miR21 may serve as novel therapeutic targets for CML blast crisis; and demethylation drugs might also have potential clinical application in treating CML blast crisis.

Xu G, Meng L, Yuan D, et al.
MEG3/miR‑21 axis affects cell mobility by suppressing epithelial‑mesenchymal transition in gastric cancer.
Oncol Rep. 2018; 40(1):39-48 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
The prognosis of patients with gastric cancer remains poor mainly due to distant metastasis. Maternally expressed gene 3 (MEG3), a long non‑coding RNA (lncRNA), is downregulated in various tumor tissues and suppresses tumor progression. miR‑21 is a microRNA which is expressed highly in tumor tissues. In the present study, we investigated the relationship between MEG3 and miR‑21 in regards to the cell mobility of gastric cancer. Our data demonstrated that MEG3 was downregulated while miR‑21 was upregulated in gastric cancer tissues and cell lines by qRT‑PCR. Overexpression of MEG3 suppressed cell mobility of gastric cancer cells (AGS) by downregulating the expression of MMP‑3, MMP‑9 and VEGF. As shown by western blot analysis, overexpression of MEG3 also suppressed epithelial‑mesenchymal transition (EMT) by increasing the expression of an epithelial marker (E‑cadherin) and downregulating the expression of mesenchymal markers (N‑cadherin, Snail and β‑catenin), indicating that MEG3 suppressed cell mobility through the inhibition of EMT in gastric cancer. The expression of miR‑21 was negatively regulated by MEG3 and overexpression of miR‑21 promoted cell mobility of AGS through activation of EMT. Co‑transfection of lncRNA‑MEG3 and miR‑21 mimic counteracted the inhibitory effect on the cell mobility attributed to MEG3, suggesting that the MEG3/miR‑21 axis affects cell mobility by suppressing EMT in gastric cancer. Using a mouse xenograft tumor model, we found that the overexpression of MEG3 suppressed tumor growth and metastasis while overexpression of miR‑21 had the opposite effects. The MEG3/miR‑21 axis affected gastric cancer growth and metastasis through inhibition of EMT in vivo. In conclusion, we demonstrated that the MEG3/miR‑21 axis participates in the tumor progression and metastasis of gastric cancer through the regulation of EMT.

Song J, Ye A, Jiang E, et al.
Reconstruction and analysis of the aberrant lncRNA-miRNA-mRNA network based on competitive endogenous RNA in CESC.
J Cell Biochem. 2018; 119(8):6665-6673 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
A growing body of studies has demonstrated that long non-coding RNA (lncRNA) are regarded as the primary section of the ceRNA network. This is thought to be the case owing to its regulation of protein-coding gene expression by functioning as miRNA sponges. However, functional roles and regulatory mechanisms of lncRNA-mediated ceRNA in cervical squamous cell carcinoma (CESC), as well as their use for potential prediction of CESC prognosis, remains unknown. The aberrant expression profiles of mRNA, lncRNA, and miRNA of 306 cervical squamous cancer tissues and three adjacent cervical tissues were obtained from the TCGA database. A lncRNA-mRNA-miRNA ceRNA network in CESC was constructed. Meanwhile, Gene Ontology (GO) and KEGG pathway analysis were performed using Cytoscape plug-in BinGo and DAVID database. We identified a total of 493 lncRNA, 70 miRNA, and 1921 mRNA as differentially expressed profiles. An aberrant lncRNA-mRNA-miRNA ceRNA network was constructed in CESC, it was composed of 50 DElncRNA, 18 DEmiRNA, and 81 DEmRNA. According to the overall survival analysis, 3 out of 50 lncRNA, 10 out of 81 mRNA, and 1 out of 18 miRNA functioned as prognostic biomarkers for patients with CESC (P value < 0.05). We extracted the sub-network in the ceRNA network and found that two novel lncRNA were recognized as key genes. These included lncRNA MEG3 and lncRNA ADAMTS9-AS2. The present study provides a new insight into a better understanding of the lncRNA-related ceRNA network in CESC, and the novel recognized ceRNA network will help us to improve our understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of CESC.

Zhu Y, Chen P, Gao Y, et al.
MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin.
EBioMedicine. 2018; 30:148-157 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732-1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over-expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1α,25-(OH)

Wu WJ, Shen Y, Sui J, et al.
Integrated analysis of long non‑coding RNA competing interactions revealed potential biomarkers in cervical cancer: Based on a public database.
Mol Med Rep. 2018; 17(6):7845-7858 [PubMed] Related Publications
Cervical cancer (CC) is a common gynecological malignancy in women worldwide. Using an RNA sequencing profile from The Cancer Genome Atlas (TCGA) and the CC patient information, the aim of the present study was to identify potential long non‑coding RNA (lncRNA) biomarkers of CC using bioinformatics analysis and building a competing endogenous RNA (ceRNA) co‑expression network. Results indicated several CC‑specific lncRNAs, which were associated with CC clinical information and selected some of them for validation and evaluated their diagnostic values. Bioinformatics analysis identified 51 CC‑specific lncRNAs (fold‑change >2 and P<0.05), and 42 of these were included in ceRNA network consisting of lncRNA‑miRNA‑mRNA interactions. Further analyses revealed that differential expression levels of 19 lncRNAs were significantly associated with different clinical features (P<0.05). A total of 11 key lncRNAs in the ceRNA network for reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis to detect their expression levels in 31 pairs of CC clinical samples. The results indicated that 7 lncRNAs were upregulated and 4 lncRNAs were downregulated in CC patients. The fold‑changes between the RT‑qPCR experiments and the TCGA bioinformatics analyses were the same. Furthermore, the area under the receiver operating characteristic (ROC) curve of four lncRNAs (EMX20S, MEG3, SYS1‑DBNDD2 and MIR9‑3HG) indicated that their combined use may have a significant diagnostic value in CC (P<0.05). To the best of our knowledge, the present study is the first to have identified CC‑specific lncRNAs to construct a ceRNA network and has also provided new insights for further investigation of a lncRNA‑associated ceRNA network in CC. In additon, the verification results suggested that the method of bioinformatics analysis and screening of lncRNAs was accurate and reliable. To conclude, the use of multiple lncRNAs may thus improve diagnostic efficacy in CC. In addition, these specific lncRNAs may serve as new candidate biomarkers for clinical diagnosis, classification and prognosis of CC.

Zhuo ZJ, Zhang R, Zhang J, et al.
Associations between lncRNA
Aging (Albany NY). 2018; 10(3):481-491 [PubMed] Article available free on PMC after 23/11/2019 Related Publications
Neuroblastoma is the third most common childhood cancer after leukemias and cancer of the central nervous system. Long noncoding RNA

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