MEG3

Gene Summary

Gene:MEG3; maternally expressed 3 (non-protein coding)
Aliases: GTL2, FP504, prebp1, PRO0518, PRO2160, LINC00023, NCRNA00023, onco-lncRNA-83
Location:14q32.2
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: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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)

Sun L, Yang C, Xu J, et al.
Long Noncoding RNA EWSAT1 Promotes Osteosarcoma Cell Growth and Metastasis Through Suppression of MEG3 Expression.
DNA Cell Biol. 2016; 35(12):812-818 [PubMed] Related Publications
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Long noncoding RNAs (lncRNAs) are a class of transcriptional products of the genome without protein-coding potential. Recently, lncRNA Ewing sarcoma-associated transcript 1 (EWSAT1) was functionally identified in Ewing sarcoma, a highly aggressive primary pediatric bone tumor. However, whether EWSAT1 plays a role in OS remains unclear. In the present study, gain- and loss-of-function assays demonstrated that EWSAT1 enhanced OS cell proliferation, migration, and invasion. Further mechanistic studies found that EWSAT1 positively regulated lncRNA MEG3 expression in the transcriptional level. Finally, we observed that EWSAT1 facilitates OS cell growth and metastasis through regulation of MEG3, suggesting that EWSAT1-MEG3 axis might be a promising target for OS treatment.

Ni S, Zhao X, Ouyang L
Long non-coding RNA expression profile in vulvar squamous cell carcinoma and its clinical significance.
Oncol Rep. 2016; 36(5):2571-2578 [PubMed] Related Publications
Researchers have recently demonstrated the key role of long non-coding RNAs (lncRNAs) in regulating embryogenesis and gene expression. However, the exact mechanism used by lncRNAs in carcinogenesis is still unclear. In particular, studies regarding the role of lncRNAs in vulvar squamous cell carcinomas (VSCCs) are limited. Using microarray analysis, the genome-wide expression profile of lncRNAs was investigated in four paired VSCCs and adjacent normal vulvar tissues. Accordingly, several novel lncRNA candidates (HOAIR, MALAT1, MEG3, NEAT1, MIR31HG and LINC00478) were chosen for further study and real-time reverse transcription PCR (RT-PCR) was used to confirm the expression levels among 35 tissue samples. A panel of dysregulated lncRNAs (MEG3 and MALAT1) were also identified as potential biomarkers as they also correlated with VSCC carcinogenesis. In summary, the results revealed that aberrantly expressed lncRNAs may be a factor in VSCC pathogenesis, potentially providing new biomarkers and therapeutic targets for VSCC.

Guo Q, Qian Z, Yan D, et al.
LncRNA-MEG3 inhibits cell proliferation of endometrial carcinoma by repressing Notch signaling.
Biomed Pharmacother. 2016; 82:589-94 [PubMed] Related Publications
BACKGROUND: The long non-coding RNA MEG3 has shown functional role as a tumor suppressor in many cancer types, excluding endometrial carcinoma (EC). Thus, this study tried to reveal the MEG3 dysregulation in EC samples and potential functional mechanism due to its regulation on Notch signaling pathway.
METHODS: The expression profiles of MEG3 and two Notch signaling molecules, Notch1 and Hes1, were detected in both EC tissues and cell lines through real time PCR and western blot analysis. Lentiviral vector carrying whole MEG3 transcript or shRNA targeting MEG3 (shMEG3) was transfected for MEG3 dysfunction studies, and cell proliferation was analyzed through MTT and colony-formation assays. Xenograft models were also established by subcutaneous implantation and tumor growth was compared under MEG3 dysregulation.
RESULTS: Significant downregulation of MEG3 was observed in EC samples compared to control, while the protein levels of Notch1 and Hes1 were both upregulated. Cell proliferation was obviously inhibited by MEG3 overexpression, while opposite improved result was obtained in MEG3 knockout cells. Interestingly, MEG3-induced changes could be reversed by Notch1 regulators. Moreover, MEG3 overexpressing tumors showed strongly repressed growth in vivo, along with Notch signaling inhibition.
CONCLUSION: Downregulated MEG3 exhibited an anti-proliferative role in EC by repressing Notch signaling pathway.

Balci T, Yilmaz Susluer S, Kayabasi C, et al.
Analysis of dysregulated long non-coding RNA expressions in glioblastoma cells.
Gene. 2016; 590(1):120-2 [PubMed] Related Publications
Long non coding RNAs (lncRNAs) are associated with various biological roles such as embryogenesis, stem cell biology, cellular development and present specific tissue expression profiles. Aberrant expression of lncRNAs are thought to play a critical role in the progression and development of various cancer types, including gliomas. Glioblastomas (GBM) are common and malignant primary brain tumours. Brain cancer stem cells (BCSC) are isolated from both low and high-grade tumours in adults and children, by cell fraction which express neuronal stem cell surface marker CD133. The purpose of this study was to investigate the expression profiles of lncRNAs in brain tumour cells and determine its potential biological function. For this purpose, U118MG-U87MG; GBM stem cell series were used. Human parental brain cancer cells were included as the control group; the expressions of disease related human lncRNA profiles were studied by LightCycler 480 real-time PCR. Expression profiles of 83 lncRNA genes were analyzed for a significant dysregulation, compared to the control cells. Among lncRNAs, 51 lncRNA genes down-regulated, while 8 lncRNA genes were up-regulated. PCAT-1 (-2.36), MEG3 (-5.34), HOTAIR (-2.48) lncRNAs showed low expression in glioblastoma compared to the human (parental) brain cancer stem cells, indicating their role as tumour suppressor genes on gliomas. As a result, significant changes for anti-cancer gene expressions were detected with disease-related human lncRNA array plates. Identification of novel target genes may lead to promising developments in human brain cancer treatment.

Cao X, Zhuang S, Hu Y, et al.
Associations between polymorphisms of long non-coding RNA MEG3 and risk of colorectal cancer in Chinese.
Oncotarget. 2016; 7(14):19054-9 [PubMed] Free Access to Full Article Related Publications
Maternally expressed gene 3 (MEG3), a long non-coding RNA (lncRNA), is involved in cancer development and metastasis. The objective of the present study was to evaluate whether common single nucleotide polymorphisms (SNPs) in MEG3 could be related with colorectal cancer risk in Chinese. We genotyped six tagSNPs of MEG3 in a colorectal cancer case-control study including 518 cases and 527 control subjects. Multivariate logistic regression analysis was applied to calculate adjusted odds ratios (ORs). We found that MEG3 rs7158663 AA genotype, but not GA genotype, had significant increased colorectal cancer risk, compared with GG genotype (OR = 1.96 and P = 0.006 for AA versus GG, and OR = 1.20 and P = 0.171 for GA versus GG). Further stratified analysis indicated that the increased risk was significantly correlated with individuals with age ≤ 60 and family history of cancer. However, there was no significant association between rs7158663 and colorectal tumor site and stage (P = 0.842 for tumor site, and P = 0.601 for tumor stage). These results demonstrate that genetic variants in MEG3 may contribute to the development and risk of colorectal cancer. Further studies are required to confirm these findings.

Hu D, Su C, Jiang M, et al.
Fenofibrate inhibited pancreatic cancer cells proliferation via activation of p53 mediated by upregulation of LncRNA MEG3.
Biochem Biophys Res Commun. 2016; 471(2):290-5 [PubMed] Related Publications
There is still no suitable drug for pancreatic cancer treatment, which is one of the most aggressive human tumors. Maternally expressed gene 3 (MEG3), a LncRNA, has been suggested as a tumor suppressor in a range of human tumors. Studies found fenofibrate exerted anti-tumor roles in various human cancer cell lines. However, its role in pancreatic cancer remains unknown. The present study aimed to explore the impacts of fenofibrate on pancreatic cancer cell lines, and to investigate MEG3 role in its anti-tumor mechanisms. We used MTT assay to determine cells proliferation, genome-wide LncRNA microarray analysis to identify differently expressed LncRNAs, siRNA or pCDNA-MEG3 transfection to interfere or upregulate MEG3 expression, western blot to detect protein levels, real-time PCR to determine MEG3 level. Fenofibrate significantly inhibited proliferation of pancreatic cancer cells, increased MEG3 expression and p53 levels. Moreover, knockdown of MEG3 attenuated cytotoxicity induced by fenofibrate. Furthermore, overexpression of MEG3 induced cells death and increased p53 expression. Our results indicated fenofibrate inhibited pancreatic cancer cells proliferation via activation of p53 mediated by upregulation of MEG3.

Liu B, Shen ED, Liao MM, et al.
Expression and mechanisms of long non-coding RNA genes MEG3 and ANRIL in gallbladder cancer.
Tumour Biol. 2016; 37(7):9875-86 [PubMed] Related Publications
The objective of this study was to investigate the expression, proliferation, and apoptosis function of long-chain non-coding RNA maternally expressed gene 3 (MEG3) and antisense non-coding RNA at the INK4 locus (ANRIL) in gallbladder cancer (GBC) tissues. GBC tissues and adjacent normal samples were collected from 84 patients from January 2008 to June 2010. Empty vector, pcDNA-MEG3, and pcDNA-ANRIL vectors were transfected into GBC-SD and QBC939 cells. An MTT assay, real-time quantitative polymerase chain reaction (RT-qPCR), flow cytometry, Western blotting, and immunohistochemistry were applied. The effects of MEG3 and ANRIL were also verified in mice. Compared with normal tissues, the expression of MEG3 was significantly lower in GBC tissues, whereas the expression of ANRIL was significantly higher (both P < 0.05). The overexpression of MEG3 and underexpression of ANRIL were significantly associated with GBC prognosis (both P < 0.05). The expressions of MEG3 and ANRIL were higher in pcDNA-MEG3 and pcDNA-ANRIL-transfected cells than in empty vector-transfected cells in vitro (both P < 0.05). Most of the pcDNA-MEG3-transfected cells were in the G0-G1 phase, which showed reduced cell activity and clone counts and increased p53 and decreased cyclin D1, whereas the pcDNA-ANRIL-transfected cells were mostly in the S phase and showed contrasting behavior. Mice injected with pcDNA-MEG3-transfected cells had smaller and lighter tumors, decreased ki-67 levels, and increased caspase 3 levels, whereas those injected with pcDNA-ANRIL showed contrasting results (all P < 0.05). MEG3 can inhibit the proliferation of GBC cells and promote apoptosis, whereas ANRIL can improve the proliferation of gallbladder cells and inhibit apoptosis. Collectively, our results suggest that therapeutic strategies directed toward upregulating MEG3 and downregulating ANRIL may be clinically relevant for the inhibition of GBC deterioration.

Li T, Mo X, Fu L, et al.
Molecular mechanisms of long noncoding RNAs on gastric cancer.
Oncotarget. 2016; 7(8):8601-12 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.

Gong WJ, Yin JY, Li XP, et al.
Association of well-characterized lung cancer lncRNA polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response.
Tumour Biol. 2016; 37(6):8349-58 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) play important roles in carcinogenesis and drug efficacy. Platinum-based chemotherapy is first-line treatment for lung cancer chemotherapy. In this study, we aimed to investigate the association of well-characterized lung cancer lncRNA genetic polymorphisms with the lung cancer susceptibility and platinum-based chemotherapy response. A total of 498 lung cancer patients and 213 healthy controls were recruited in the study. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Thirteen polymorphisms in HOXA distal transcript antisense RNA (HOTTIP), HOX transcript antisense intergenic RNA (HOTAIR), H19, CDKN2B antisense RNA 1 (ANRIL), colon cancer-associated transcript 2 (CCAT2), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and maternally expressed gene 3 (MEG3) genes were genotyped by allele-specific MALDI-TOF mass spectrometry. We found that patients with HOTTIP rs5883064 C allele or rs1859168 A allele had increased lung cancer risk (P = 0.01, P = 0.01, respectively). CCAT2 rs6983267 (P = 0.02, adenocarcinoma) and H19 rs2107425 (P = 0.02, age under 50 years) showed strong relationship with lung cancer susceptibility. CCAT2 rs6983267, H19 rs2839698, MALAT1 rs619586, and HOTAIR rs7958904 were associated with platinum-based chemotherapy response in dominant model ((P = 0.02, P = 0.04, P = 0.04, P = 0.01, respectively). ANRIL rs10120688 (P = 0.02, adenocarcinoma) and rs1333049 (P = 0.04, small-cell lung cancer), H19 rs2107425 (P = 0.02, small-cell lung cancer) and HOTAIR rs1899663 (P = 0.03, male; P = 0.03, smoker) were associated with response to platinum-based chemotherapy. HOTTIP, CCAT2, H19, HOTAIR, MALATI, ANRIL genetic polymorphisms were significantly associated with lung cancer susceptibility or platinum-based chemotherapy response. They may be potential clinical biomarkers to predict lung cancer risk and platinum-based chemotherapy response.

Li C, Liang G, Yao W, et al.
Differential expression profiles of long non-coding RNAs reveal potential biomarkers for identification of human gastric cancer.
Oncol Rep. 2016; 35(3):1529-40 [PubMed] Related Publications
Gastric cancer (GC) is one of the most lethal malignancies worldwide. To reduce its high mortality, sensitive and specific biomarkers for early detection are urgently needed. Recent studies have reported that tumor-specific long non-coding RNAs (lncRNAs) seem to be potential biomarkers for the early diagnosis and treatment of cancer. In the present study, lncRNA and mRNA expression profiling of GC specimens and their paired adjacent non-cancerous tissues was performed. Differentially expressed lncRNAs and mRNAs were identified through microarray analysis. The function of differential mRNA was determined by gene ontology and pathway analysis and the functions of lncRNAs were studied by constructing a co-expression network to find the relationships with corresponding mRNAs. We connected the co-expression network, mRNA functions, and the results of the microarray profile differential expression and selected 14 significantly differentially expressed key lncRNAs and 21 key mRNAs. Quantitative RT-PCR (qRT-PCR) was conducted to verify these key RNAs in 50 newly diagnosed GC patients. The data showed that RP5-919F19, CTD-2541M15 and UCA1 was significantly higher expressed. AP000459, LOC101928316, RP11-167N4 and LINC01071 expression was significantly lower in 30 advanced GC tumor tissues than adjacent non-tumor tissues P<0.05. Then, we further validated the above significant differential expression candidate lncRNAs in 20 early stage GC patients. Results showed that CTD-2541M15 and UCA1 were significantly higher expressed, AP000459, LINC01071 and MEG3 expression was significantly lower in 20 early stage GC patient tumor tissues than adjacent non-tumor tissues (P<0.05). In addition, expression of these lncRNAs shows gradual upward trend from early stage GC to advanced GC. Furthermore, conditional logistic regression analysis revealed the aberrant expression of CTD-2541M15, UCA1 and MEG3 closely linked with GC. There is a set of differentially expressed lncRNAs in GC which may be associated with the progression and development of GC. The differential expression profiles of lncRNAs in GC may be promising biomarkers for the early detection and early screening of high‑risk populations.

Li J, Bian EB, He XJ, et al.
Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas.
Int J Oncol. 2016; 48(2):723-33 [PubMed] Related Publications
Epigenetic regulation plays a significant role in gliomas. However, how methylation and long non-coding RNA (lncRNA) cooperates to regulate gliomas progression is largely unknown. In this investigation we showed that the downregulation of MEG3 expression due to hypermethylation of MEG3 was observed in gliomas tissues. Treatment of glioma cells with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) decreased aberrant hypermethylation of the MEG3 promoter and prevented the loss of MEG3 expression. In addition, DNMT1 was involved in MEG3 promoter methylation, and was inversely correlated with MEG3 expression in gliomas. The inhibition of DNMT1 repressed the proliferation, clone formation, and induced apoptosis in glioma cells. Importantly, the inhibition of DNMT1 contributed to the activation of p53 pathways in gliomas cells. These results suggest that DNMT1-mediated MEG3 hypermethylation caused the loss of MEG3 expression, followed by the inhibition of the p53 pathways in gliomas.

Gao Y, Lu X
Decreased expression of MEG3 contributes to retinoblastoma progression and affects retinoblastoma cell growth by regulating the activity of Wnt/β-catenin pathway.
Tumour Biol. 2016; 37(2):1461-9 [PubMed] Related Publications
The aberrant expression of MEG3 has been found in some types of cancers; however, little is known concerning the function of MEG3 in retinoblastoma. To elucidate the roles of MEG3 in retinoblastoma, MEG3 expression was quantified in 63 retinoblastoma samples and corresponding nontumor tissues in this work. Moreover, retinoblastoma cell lines were transfected with pcDNA3.1-MEG3 or si-MEG3, after which proliferation, apoptosis, and expression of β-catenin were assayed. TOP-Flash reporter assay was also used to investigate the activity of the Wnt/β-catenin pathway. The results showed that MEG3 was downregulated in retinoblastoma tissues, and the level of MEG3 was negatively associated with IIRC stages and nodal or distant metastasis. More importantly, Kaplan-Meier survival analysis demonstrated that patients with low MEG3 expression had poorer survival and multivariate Cox regression analysis revealed that MEG3 was an independent prognostic factor in retinoblastoma patients. We also observed that MEG3 expression can be modulated by DNA methylation by using 5-aza-CdR treatment. In addition, overexpression of MEG3 suppressed proliferation, promoted apoptosis, and influences the activity of the Wnt/β-catenin pathway in retinoblastoma cell lines. Furthermore, we found that Wnt/β-catenin pathway activator rescued the anticancer effect of MEG3 in retinoblastoma. In conclusion, our study for the first time demonstrated that MEG3 was a tumor suppressor by negatively regulating the activity of the Wnt/β-catenin pathway in the progression of retinoblastoma and might serve as a prognostic biomarker and molecular therapeutic target.

Liu LX, Deng W, Zhou XT, et al.
The mechanism of adenosine-mediated activation of lncRNA MEG3 and its antitumor effects in human hepatoma cells.
Int J Oncol. 2016; 48(1):421-9 [PubMed] Related Publications
Long non-coding RNA MEG3 is suggested to function as a tumor suppressor. However, the activation mechanism of MEG3 is still not well understood and data are not available on its role under adenosine-induced apoptosis. In this study, HepG2 cells were treated with adenosine or 5-Aza‑cdR. Methylation status of MEG3 promoter was detected by methylation specific PCR (MSP) and MEG3 expression was determined by qRT-PCR. PcDNA3.1-MEG3 recombinant plasmid was constructed and transfected to hepatoma HepG2 and Huh7 cells. Cell growth, morphological changes, cell-cycle distribution and apoptosis were analyzed by MTT assay, fluorescence microscopy and flow cytometry. The mRNA and protein expression levels were detected by qRT-PCR and western blot analysis. MEG3 binding proteins were screened by the improved MS2 biotin tagged RNA affinity purification method. The co-expression network of MEG3 was generated by GO analysis and ILF3 was identified as MEG3 binding protein by RNA pulldown and western blot analysis. Both adenosine and 5-Aza-CdR increased MEG3 mRNA expression and the CpG island of MEG3 gene in HepG2 cells was typical hypermethylation. Ectopic expression of MEG3 inhibited hepatoma cell growth in a time-dependent manner, resulted in cell cycle arrest and induced apoptosis. Ectopic expression of MEG3 increased p53, caspase-3 mRNA and protein levels, decreased MDM2 and cyclin D1 mRNA and protein levels, as well as ILF3 protein expression in HepG2 cells. These findings are the first to identify that adenosine increases MEG3 expression by inhibition of DNA methylation and its antitumor effects is involved in MEG3 activation. ILF3 may participate in the anticancer regulation of MEG3 by interacting with MEG3.

Luo G, Wang M, Wu X, et al.
Long Non-Coding RNA MEG3 Inhibits Cell Proliferation and Induces Apoptosis in Prostate Cancer.
Cell Physiol Biochem. 2015; 37(6):2209-20 [PubMed] Related Publications
BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as cell growth, apoptosis and migration. Although downregulation of lncRNA maternally expressed gene 3 (MEG3) has been identified in several cancers, little is known about its role in prostate cancer progression. The aim of this study was to detect MEG3 expression in clinical prostate cancer tissues, investigate its biological functions in the development of prostate cancer and the underlying mechanism.
METHODS: MEG3 expression levels were detected by qRT-PCR in both tumor tissues and adjacent non-tumor tissues from 21 prostate cancer patients. The effects of MEG3 on PC3 and DU145 cells were assessed by MTT assay, colony formation assay, western blot and flow cytometry. Transfected PC3 cells were transplanted into nude mice, and the tumor growth curves were determined.
RESULTS: MEG3 decreased significantly in prostate cancer tissues relative to adjacent normal tissues. MEG3 inhibited intrinsic cell survival pathway in vitro and in vivo by reducing the protein expression of Bcl-2, enhancing Bax and activating caspase 3. We further demonstrated that MEG3 inhibited the expression of cell cycle regulatory protein Cyclin D1 and induced cell cycle arrest in G0/G1 phase.
CONCLUSIONS: Our study presents an important role of MEG3 in the molecular etiology of prostate cancer and implicates the potential application of MEG3 in prostate cancer therapy.

Zhang J, Yao T, Wang Y, et al.
Long noncoding RNA MEG3 is downregulated in cervical cancer and affects cell proliferation and apoptosis by regulating miR-21.
Cancer Biol Ther. 2016; 17(1):104-13 [PubMed] Free Access to Full Article Related Publications
Recent research has found that long noncoding RNAs (lncRNAs) were involved in various human cancers. However, the role of these lncRNAs in cervical cancer remains unexplored. Therefore, we aimed to investigate the biological function of maternally expressed gene 3 (MEG3), a cancer-related lncRNA, and its underlying mechanism in cervical cancer. In this study, MEG3 expression of 108 patients' cervical cancer tissues and adjacent normal tissues was detected by quantitative real-time PCR analysis (qRT-PCR), and the functional effect of MEG3 was determined in vitro assays. We observed that MEG3 was downregulated in cervical cancer tissues, compared to the adjacent normal tissues, and was negatively related with FIGO stages, tumor size, lymphatic metastasis, HR-HPV infection and the expression of homo sapiens microRNA-21 (miR-21). Furthermore, we focused on the function and molecular mechanism of MEG3, finding that overexpression of MEG3 reduced the level of miR-21-5p expression, causing inhibition of proliferation and increased apoptosis in cervical cancer cells. In summary, our findings indicate that MEG3 function as a tumor suppressor by regulating miR-21-5p, resulting in the inhibition of tumor growth in cervical cancer. As a result, this study improves our understanding of the function of MEG3 in cervical cancer and will help to provide new potential target sites for cervical cancer treatment.

Guo LL, Song CH, Wang P, et al.
Competing endogenous RNA networks and gastric cancer.
World J Gastroenterol. 2015; 21(41):11680-7 [PubMed] Free Access to Full Article Related Publications
Recent studies have showed that RNAs regulate each other with microRNA (miRNA) response elements (MREs) and this mechanism is known as "competing endogenous RNA (ceRNA)" hypothesis. Long non-coding RNAs (lncRNAs) are supposed to play important roles in cancer. Compelling evidence suggests that lncRNAs can interact with miRNAs and regulate the expression of miRNAs as ceRNAs. Several lncRNAs such as H19, HOTAIR and MEG3 have been found to be associated with miRNAs in gastric cancer (GC), generating regulatory crosstalk across the transcriptome. These MRE sharing elements implicated in the ceRNA networks (ceRNETs) are able to regulate mRNA expression. The ceRNA regulatory networks including mRNAs, miRNAs, lncRNAs and circular RNAs may play critical roles in tumorigenesis, and the perturbations of ceRNETs may contribute to the pathogenesis of GC.

Su L, Han D, Wu J, Huo X
Skp2 regulates non-small cell lung cancer cell growth by Meg3 and miR-3163.
Tumour Biol. 2016; 37(3):3925-31 [PubMed] Related Publications
Maternally expressed gene 3 (Meg3) encodes a long non-coding RNA that has been shown to play a role in tumorigenesis. Skp2 is a component of the E3 ubiquitin ligase SCF that specifically promotes the ubiquitination-associated degradation of CDK inhibitor p27, and has been shown to promote cancer cell growth in different types of cancers, including non-small cell lung cancer (NSCLC). Nevertheless, a regulatory relationship between Meg3 and Skp2 has not been acknowledged. Here, we showed that NSCLC specimens had significant higher levels of Skp2 and significantly lower levels of Meg3, compared to paired non-tumor lung tissue. The levels of Meg3 and Skp2 were inversely correlated in NSCLC specimens. Patients with low Meg3 levels had a poor survival. Overexpression of Meg3 decreased Skp2 protein and increased p27 protein, while depletion of Meg3 increased Skp2 protein and decreased p27 protein in NSCLC cells, without altering Skp2 mRNA. These data suggest that the Skp2 may be regulated by Meg3 at post-transcriptional level. Bioinformatics analyses showed that miR-3163 bound to 3'-UTR of Skp2 mRNA in NSCLC cells to inhibit its translation, which was supported by luciferase reporter assay. Meg3 augmented the effects of miR-3163 on Skp2 mRNA, possibly through binding-induced function enhancement, which was supported by the double fluorescent in situ hybridization showing co-localized intracellular Meg3 and miR-3163 signals in NSCLC cells. The miR-3163 levels in NSCLC were not different from in NT, suggesting that the regulation of Skp2 in NSCLC by miR-3163 may require coordination of Meg3. Thus, our data suggest that Meg3 and miR-3163 may coordinate suppression of translation of Skp2 mRNA in NSCLC cells to inhibit NSCLC cell growth.

Zhu J, Liu S, Ye F, et al.
Long Noncoding RNA MEG3 Interacts with p53 Protein and Regulates Partial p53 Target Genes in Hepatoma Cells.
PLoS One. 2015; 10(10):e0139790 [PubMed] Free Access to Full Article Related Publications
Maternally Expressed Gene 3 (MEG3) encodes a lncRNA which is suggested to function as a tumor suppressor. Previous studies suggested that MEG3 functioned through activation of p53, however, the functional properties of MEG3 remain obscure and their relevance to human diseases is under continuous investigation. Here, we try to illuminate the relationship of MEG3 and p53, and the consequence in hepatoma cells. We find that transfection of expression construct of MEG3 enhances stability and transcriptional activity of p53. Deletion analysis of MEG3 confirms that full length and intact structure of MEG3 are critical for it to activate p53-mediated transactivation. Interestingly, our results demonstrate for the first time that MEG3 can interact with p53 DNA binding domain and various p53 target genes are deregulated after overexpression of MEG3 in hepatoma cells. Furthermore, results of qRT-PCR have shown that MEG3 RNA is lost or reduced in the majority of HCC samples compared with adjacent non-tumorous samples. Ectopic expression of MEG3 in hepatoma cells significantly inhibits proliferation and induces apoptosis. In conclusion, our data demonstrates that MEG3 functions as a tumor suppressor in hepatoma cells through interacting with p53 protein to activate p53-mediated transcriptional activity and influence the expression of partial p53 target genes.

Li L, Xu-Monette ZY, Ok CY, et al.
Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma.
Oncotarget. 2015; 6(27):23157-80 [PubMed] Free Access to Full Article Related Publications
Dysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2- activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications.

Zamani M, Sadeghizadeh M, Behmanesh M, Najafi F
Dendrosomal curcumin increases expression of the long non-coding RNA gene MEG3 via up-regulation of epi-miRs in hepatocellular cancer.
Phytomedicine. 2015; 22(10):961-7 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma is the fifth most common cancer worldwide, with poor prognosis and resistance to chemotherapy. This gives novel cancer treatment methods an overwhelming significance. Epigenetic therapy of cancer is useful in reversing some of the cancer defects because of reversibility of the epigenetic alterations. Non-protein coding transcripts are the major part of our transcriptome. MEG3 is a tumor suppressor long non-coding RNA being expressed in many normal tissues. Methylation of MEG3 promoter region elicits the decrease in its expression in hepatocellular cancer cells. Bioactive nutrients including curcumin offer great potential in altering DNA methylation status which is catalyzed via DNMT1, DNMT3A and 3B.
PURPOSE: Herein, we aimed to study RNA-based epigenetic effects of dendrosomal curcumin (DNC) on hepatocellular cancer (HCC).
STUDY DESIGN: To this end miRNA-dependent regulation of MEG3 expression under treatment with DNC was studied by evaluating the modulatory involvement of miR-29a for DNMT3A and 3B and miR-185 for DNMT1.
METHODS: We evaluated DNC entrance to HCC cells with the use of fluorescent characteristics of curcumin. Next we performed the MTT assay to evaluate DNC and dendrosome effects on HCC cell viability. The coding and non-coding genes expression analyses were done using quantitative-PCR.
RESULTS: In result we found that the DNC dependent overexpression of miR-29a and miR-185 (P < 0.01) can down-regulate the expression of DNMT1, 3A and 3B (P < 0.05) and subsequently overexpresses MEG3 (P < 0.05).
CONCLUSION: DNC potentially can induce DNA hypomethylation and reexpression of silenced tumor suppressor genes in HCC. These data suggest that DNC could be an effective choice for epigenetic therapy of HCC.

Chunharojrith P, Nakayama Y, Jiang X, et al.
Tumor suppression by MEG3 lncRNA in a human pituitary tumor derived cell line.
Mol Cell Endocrinol. 2015; 416:27-35 [PubMed] Free Access to Full Article Related Publications
Human clinically non-functioning pituitary adenomas (NFAs) account for approximately 40% of diagnosed pituitary tumors. Epigenetic mutations in tumor suppressive genes play an important role in NFA development. Maternally expressed gene 3 (MEG3) is a long non-coding RNA (lncRNA) and we hypothesized that it is a candidate tumor suppressor whose epigenetic silencing is specifically linked to NFA development. In this study, we introduced MEG3 expression into PDFS cells, derived from a human NFA, using both inducible and constitutively active expression systems. MEG3 expression significantly suppressed xenograft tumor growth in vivo in nude mice. When induced in culture, MEG3 caused cell cycle arrest at the G1 phase. In addition, inactivation of p53 completely abolished tumor suppression by MEG3, indicating that MEG3 tumor suppression is mediated by p53. In conclusion, our data support the hypothesis that MEG3 is a lncRNA tumor suppressor in the pituitary and its inactivation contributes to NFA development.

Peng W, Si S, Zhang Q, et al.
Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate gastric cancer progression.
J Exp Clin Cancer Res. 2015; 34:79 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have recently emerged as important regulators in governing fundamental biological processes, and many of which are likely to have functional roles in tumorigenesis. Maternally expressed gene 3 (MEG3) gene encodes a lncRNA whose expression is lost in an expanding list of primary human tumors and tumor cell lines, however its biological role and regulatory mechanism in gastric cancer (GC) development and progression are poorly defined.
METHODS: Quantitative RT-PCR analysis was used to determine whether aberrant MEG3 expression was associated with GC patients pTNM stage and pM state. Furthermore, the effect of ectopic expression of MEG3 on cell proliferation, migration, invasion and cell apoptosis was assessed by using CCK-8, wound healing, transwell invasion assays and flow cytometric analysis, respectively, in GC cell lines HGC-27 and MGC-803. Moreover, the competing endogenous RNA (ceRNA) activity of MEG3 on miR-181a was investigated via luciferase reporter assay and immunoblot analysis.
RESULTS: MEG3 is decreased in GC patients and cell lines, and its expression was associated with metastatic GC. Furthermore, ectopic expression of MEG3 in HGC-27 and MGC-803 cells inhibited cell proliferation, migration, invasion, and promoted cell apoptosis, which might be due to MEG3 sequestering oncogenic miR-181 s in GC cells. Furthermore, MEG3 could up-regulated Bcl-2 via its competing endogenous RNA (ceRNA) activity on miR-181a.
CONCLUSIONS: These findings suggest that lncRNA MEG3, a ceRNA of miR-181 s, could regulate gastric carcinogenesis and may serve as a potential target for antineoplastic therapies.

Zhou X, Ji G, Ke X, et al.
MiR-141 Inhibits Gastric Cancer Proliferation by Interacting with Long Noncoding RNA MEG3 and Down-Regulating E2F3 Expression.
Dig Dis Sci. 2015; 60(11):3271-82 [PubMed] Related Publications
BACKGROUND: MiR-141 and long noncoding RNA MEG3 have been independently reported to be tumor suppressor genes in various cancers. However, their expression has never been previously associated with gastric cancer (GC).
AIMS: To investigate the interaction of miR-141 and MEG3 in GC.
METHODS: QRT-PCR was used to detect miR-141, MEG3, and E2F3 in gastric tissues and cells. CCK-8 and flow cytometry analysis were used to detect cell functions. Western blot and luciferase activity were used to identify E2F3 as one of the direct targets of miR-141.
RESULTS: We found that expression of both miR-141 and MEG3 was significantly reduced in GC compared with levels in matched nonmalignant tissues. Positive correlation between miR-141 and MEG3 was found in both tumor tissues and control tissues. Furthermore, the over-expression of either miR-141 or MEG3 in 7901 and MKN45 cells inhibited cell proliferation and cell cycle progression and promoted cell apoptosis. E2F3 was identified as a target of miR-141, and its inhibition significantly reduced MEG3 expression. E2F3 expression was also found to be negatively associated with both MEG3 and miR-141. E2F3 over-expression partly reversed the changes caused by transfection of miR-141 mimic, and inhibition of miR-141 or MEG3 overrides MEG3- or miR-141-induced modulation of cell growth in GC.
CONCLUSIONS: These findings together suggested that miR-141 could be interacting with MEG3 and targeting E2F3, and these factors may play important anti-tumor effects in GC pathogenesis and provide therapeutic targets in the clinics.

Wang M, Huang T, Luo G, et al.
Long non-coding RNA MEG3 induces renal cell carcinoma cells apoptosis by activating the mitochondrial pathway.
J Huazhong Univ Sci Technolog Med Sci. 2015; 35(4):541-5 [PubMed] Related Publications
This study aimed to examine the effect of long non-coding RNA (LncRNA) MEG3 on the biological behaviors of renal cell carcinoma (RCC) cells 786-0 and the possible mechanism. MEG3 expression levels were detected by RT-qPCR in tumor tissues and adjacent non-tumor tissues from 29 RCC patients and in RCC lines 786-0 and SN12 and human embryonic kidney cell line 293T. Plasmids GV144-MEG3 (MEG3 overexpression plasmid) and GV144 (control plasmid) were stably transfected into 786-0 cells by using lipofectamine 2000. Cell viabilities were determined by MTT, cell apoptosis rates by flow cytometry following PE Annexin V and 7AAD staining, apoptosis-related protein expressions by Western blotting, and Bcl-2 mRNA by RT-qPCR in the transfected cells. The results showed that MEG3 was evidently downregulated in RCC tissues (P<0.05) and RCC cell lines (P<0.05). The viabilities of 786-0 cells were decreased significantly after transfection with GV144-MEG3 for over 24 h (P<0.05). Consistently, the apoptosis rate was significantly increased in 786-0 cells transfected with GV144-MEG3 for 48 h (P<0.05). Furthermore, overexpression of MEG3 could reduce the expression of Bcl-2 and procaspase-9 proteins, enhance the expression of cleaved caspase-9 protein, and promote the release of cytochrome c protein to cytoplasm (P<0.05). Additionally, Bcl-2 mRNA level was declined by MEG3 overexpression (P<0.05). It was concluded that MEG3 induces the apoptosis of RCC cells possibly by activating the mitochondrial pathway.

Yang Z, Lu Y, Xu Q, et al.
HULC and H19 Played Different Roles in Overall and Disease-Free Survival from Hepatocellular Carcinoma after Curative Hepatectomy: A Preliminary Analysis from Gene Expression Omnibus.
Dis Markers. 2015; 2015:191029 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: This study aimed to evaluate the relationships between long noncoding RNAs (lncRNAs) in tumor tissues and hepatocellular carcinoma (HCC) aggressiveness and survival.
METHODS: We correlated the lncRNAs in tumor tissues with HCC survival and clinicopathological features based on Gene Expression Omnibus expression profile GSE36376.
RESULTS: Eight lncRNAs and 240 HCC patients were included. Cox regression analysis indicated that HULC was a positive factor for HCC overall survival (HR = 0.885, 95% CI = 0.797-0.983, and P = 0.023) and disease-free survival time (HR = 0.913, 95% CI = 0.835-0.998, and P = 0.045). H19 and UCA1 were both demonstrated to be risk factors of HCC disease-free survival in multivariate Cox model (HR = 1.071, 95% CI = 1.01-1.137, and P = 0.022 and HR = 2.4, 95% CI = 1.092-5.273, and P = 0.029, resp.). But Kaplan-Meier method showed no significant association between UCA1 and HCC disease-free survival (log rank P = 0.616). Logistic regression demonstrated that H19 was overexpressed in HBV-infected patients (OR = 1.14, 95% CI = 1.008-1.29, and P = 0.037). HULC had a significant association with vascular invasion (OR = 0.648, 95% CI = 0.523-0.803, and P < 0.001). H19 and MEG3 were both considered to be risk factors for high AFP level (OR = 1.45, 95% CI = 1.277-1.646, and P < 0.001 and OR = 1.613, 95% CI = 1.1-2.365, and P = 0.014, resp.).
CONCLUSIONS: Contributing to decreased susceptibility to vascular invasion, upregulation of HULC in tumor tissues was positively associated with HCC survival. In contrast, H19 overexpression might be risk factor for HCC aggressiveness and poor outcomes.

Xia Y, He Z, Liu B, et al.
Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/β-catenin signaling pathway.
Mol Med Rep. 2015; 12(3):4530-7 [PubMed] Related Publications
Maternally expressed gene 3 (Meg3) has been shown to promote tumor progression. However, the role of Meg3 in the development of a chemoresistant phenotype of human lung cancer has remains. Reverse transcription‑quantitative polymerase chain reaction analysis was used to determine the expression of Meg3. Flow cytometric analysis and MTT assay were also used to investigate the cell cycle and apoptosis. The present study detected that the expression levels of Meg3 were significantly lower in cisplatin‑resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. Furthermore, upregulation of Meg3 was able to re‑sensitize the A549/DDP cells to cisplatin in vitro. Whereas downregulation of Meg3, by RNA interference, decreased the sensitivity of A549 cells to cisplatin. The results of the present study also demonstrated that the Meg3‑mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, β‑catenin and survivin, which is a target gene of the WNT/β‑catenin signaling pathway. In conclusion, these results suggested that Meg3 may have a crucial role in the development of cisplatin resistance in non-small cell lung cancer.

Liu J, Wan L, Lu K, et al.
The Long Noncoding RNA MEG3 Contributes to Cisplatin Resistance of Human Lung Adenocarcinoma.
PLoS One. 2015; 10(5):e0114586 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemotherapy drug resistance. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes an lncRNA, and decreased MEG3 expression plays an important role in multiple cancers. However, its biological role in the development of the chemoresistance phenotype of human lung adenocarcinoma (LAD) is unknown. This study aimed to observe the expression of MEG3 in LAD and to evaluate its biological role and clinical significance in the resistance of LAD cells to cisplatin. MEG3 expression was markedly decreased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by an lncRNA microarray. MEG3 overexpression in A549/DDP cells increased their chemosensitivity to cisplatin both in vitro and in vivo by inhibiting cell proliferation and inducing apoptosis. By contrast, MEG3 knockdown in A549 cells decreased the chemosensitivity. Moreover, MEG3 was decreased in cisplatin-insensitive LAD tissues while p53 protein levels were decreased and Bcl-xl protein levels increased. Furthermore, patients with lower levels of MEG3 expression showed worse responses to cisplatin-based chemotherapy. These findings demonstrate that MEG3 is significantly downregulated in LAD and partially regulates the cisplatin resistance of LAD cells through the control of p53 and Bcl-xl expression. Thus, MEG3 may represent a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy.

Zhuang W, Ge X, Yang S, et al.
Upregulation of lncRNA MEG3 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells From Multiple Myeloma Patients By Targeting BMP4 Transcription.
Stem Cells. 2015; 33(6):1985-97 [PubMed] Related Publications
Multiple myeloma (MM) is characterized by the impaired osteogenic differentiation of mesenchymal stromal cells (MSCs). However, the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) are emerging as important regulatory molecules in tumor-suppressor and oncogenic pathways. Here we showed that MSCs from MM expressed less lncRNA MEG3 relative to those from normal donors during osteogenic differentiation. To evaluate the effect of MEG3 on osteogenesis, bone marrow MSCs with enhanced or reduced MEG3 were prepared. We observed that MEG3 knockdown significantly reduced the expression of key osteogenic markers, including Runt-related transcription factor 2, osterix, and osteocalcin, while overexpression of MEG3 enhanced their expression. Additionally, MEG3 knockdown decreased BMP4 transcription. Here we showed that MEG3 was critical for SOX2 transcriptional repression of the BMP4. MEG3, which is located near the BMP4 gene, could dissociate the transcription factor SOX2 from the BMP4 promoter. A stable complex containing the MEG3, SOX2, and the SOX2 consensus site of BMP4 suggested that MEG3 activated transcriptional activity by directly influencing SOX2 activity. By using assays such as luciferase, chromatin immunoprecipitation, and RNA immunoprecipitation, we showed that MEG3 had a critical function in a mechanism of promoter-specific transcriptional activation. These results suggested that MEG3 played an essential role in osteogenic differentiation in bone marrow MSCs, partly by activating BMP4 transcription. Our data provided novel evidence for the biological and clinical significance of lncRNA MEG3 expression as a potential biomarker for identifying patients with MM and as a potential therapeutic target in MM.

Liu Q, Sun S, Yu W, et al.
Altered expression of long non-coding RNAs during genotoxic stress-induced cell death in human glioma cells.
J Neurooncol. 2015; 122(2):283-92 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs), a recently discovered class of non-coding genes, are transcribed throughout the genome. Emerging evidence suggests that lncRNAs may be involved in modulating various aspects of tumor biology, including regulating gene activity in response to external stimuli or DNA damage. No data are available regarding the expression of lncRNAs during genotoxic stress-induced apoptosis and/or necrosis in human glioma cells. In this study, we detected a change in the expression of specific candidate lncRNAs (neat1, GAS5, TUG1, BC200, Malat1, MEG3, MIR155HG, PAR5, and ST7OT1) during DNA damage-induced apoptosis in human glioma cell lines (U251 and U87) using doxorubicin (DOX) and resveratrol (RES). We also detected the expression pattern of these lncRNAs in human glioma cell lines under necrosis induced using an increased dose of DOX. Our results reveal that the lncRNA expression patterns are distinct between genotoxic stress-induced apoptosis and necrosis in human glioma cells. The sets of lncRNA expressed during genotoxic stress-induced apoptosis were DNA-damaging agent-specific. Generally, MEG3 and ST7OT1 are up-regulated in both cell lines under apoptosis induced using both agents. The induction of GAS5 is only clearly detected during DOX-induced apoptosis, whereas the up-regulation of neat1 and MIR155HG is only found during RES-induced apoptosis in both cell lines. However, TUG1, BC200 and MIR155HG are down regulated when necrosis is induced using a high dose of DOX in both cell lines. In conclusion, our findings suggest that the distinct regulation of lncRNAs may possibly involve in the process of cellular defense against genotoxic agents.

Zhuo H, Tang J, Lin Z, et al.
The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma.
Mol Carcinog. 2016; 55(2):209-19 [PubMed] Related Publications
MEG3 as a tumor suppressor has been reported to be linked with pathogenesis of malignancies including hepatocellular carcinoma (HCC). However, the mechanism of MEG3 in HCC still remains unclear. In our study, the aberrant decreased level of MEG3 in 72 tumor tissues obtained from HCC patients and cell lines was examined by using real-time PCR. The inhibition affection in proliferation and inducing affection in apoptosis was further confirmed in vivo and vitro, we also demonstrated that MEG3 regulates HCC cell proliferation and apoptosis partially via the accumulation of p53. Besides, the hypermethylation of MEG3 in promoter region was identified by bisulfite sequencing while MEG3 increased with the inhibition of methylation. Subsequently, UHRF1, a new identified oncogene which is required for DNA methylation and recruits, was investigated. A negative correlation of MEG3 and UHRF1 expression was verified in primary HCC tissues. Down-regulation of UHRF1 induced MEG3 expression in HCC cell lines, which could be reversed by the up-regulation of UHRF1. In addition, up-regulation of MEG3 in HCC cells partially diminished the promotion of proliferation induced by UHRF1. Moreover, Kaplan-Meier analysis demonstrated that the patients with low expression of MEG3 indicated worse overall and relapse-free survivals compared with high expression of MEG3. Cox proportional hazards analyses showed that MEG3 expression was an independent prognostic factor for HCC patients. In conclusion, we demonstrated MEG3, acting as a potential biomarker in predicting the prognosis of HCC, was regulated by UHRF1 via recruiting DNMT1 and regulated p53 expression.

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