Tumor Biology

, Volume 37, Issue 12, pp 16259–16267 | Cite as

The long non-coding RNA maternally expressed gene 3 activates p53 and is downregulated in esophageal squamous cell cancer

Original Article


Esophageal squamous cell cancer (ESCC) is an aggressive malignancy with poor survival. Long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and cancer progression; hence, lncRNAs are also involved in the development and progression of ESCC. In this study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to investigate expression of lncRNA, maternally expressed gene 3 (MEG3) in ESCC. Ectopic expression of MEG3 was performed in ESCC cell lines. Proliferation and apoptosis of ESCC cell lines were analyzed after ectopic expression of MEG3. We found MEG3 was significantly downregulated in ESCC tissues compared with normal tissues by qRT-PCR. Low expression of MEG3 was correlated with lymph node metastasis and advanced TNM stages of ESCC patients and indicated shorter survival (HR = 0.471, 95 % CI 0.234–0.950, P = 0.035), which was confirmed by The Cancer Genome Atlas (TCGA) esophageal cancer dataset. DNA-demethylating agent (5-aza-2-deoxy-cytidine (5-aza-CdR)) treatment significantly increased MEG3 expression level in ESCC cells, and TCGA esophageal cancer dataset also showed that DNA methylation of MEG3 predicted survival. Ectopic expression of MEG3 in ESCC cells inhibited cell proliferation, promoted apoptosis, and suppressed metastasis. Further investigation showed enforced expression of MEG3 activated p53 and its target genes by downregulation of mouse double minute 2 homolog (MDM2). Overall, our study indicated that MEG3 expression loss is common in ESCC and MEG3 could activate p53 and predict prognosis in ESCC.


ESCC MEG3 Prognosis p53 




Compliance with ethical standards

The study was approved by the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University. The written informed consent was obtained from every patient.

Conflicts of interest



  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Qi YJ, Chao WX, Chiu JF. An overview of esophageal squamous cell carcinoma proteomics. J Proteome. 2012;75(11):3129–37. doi: 10.1016/j.jprot.2012.04.025.CrossRefGoogle Scholar
  3. 3.
    Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol. 2007;17(1):2–9. doi: 10.1016/j.semradonc.2006.09.003.CrossRefPubMedGoogle Scholar
  4. 4.
    Yang L, Parkin DM, Ferlay J, Li L, Chen Y. Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol Biomark Prev. 2005;14(1):243–50.Google Scholar
  5. 5.
    Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629–41. doi: 10.1016/j.cell.2009.02.006.CrossRefPubMedGoogle Scholar
  6. 6.
    Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23(13):1494–504. doi: 10.1101/gad.1800909.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Qiu MT, JW H, Yin R, Xu L. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol. 2013;34(2):613–20. doi: 10.1007/s13277-013-0658-6.CrossRefPubMedGoogle Scholar
  8. 8.
    Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–74. doi: 10.1038/nrg3074.CrossRefPubMedGoogle Scholar
  9. 9.
    Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71(1):3–7. doi: 10.1158/0008-5472.CAN-10-2483.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Schmidt LH, Spieker T, Koschmieder S, Schaffers S, Humberg J, Jungen D, et al. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol. 2011;6(12):1984–92. doi: 10.1097/JTO.0b013e3182307eac.CrossRefPubMedGoogle Scholar
  11. 11.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6. doi: 10.1038/nature08975.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, et al. ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011;147(4):773–88. doi: 10.1016/j.cell.2011.08.054.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512(7512):82–6. doi: 10.1038/nature13311.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Li W, Zheng J, Deng J, You Y, Wu H, Li N, et al. Increased levels of the long intergenic non-protein coding RNA POU3F3 promote DNA methylation in esophageal squamous cell carcinoma cells. Gastroenterology. 2014;146(7):1714–26 e5. doi: 10.1053/j.gastro.2014.03.002.CrossRefPubMedGoogle Scholar
  15. 15.
    Benetatos L, Vartholomatos G, Hatzimichael E. MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer. 2011;129(4):773–9. doi: 10.1002/ijc.26052.CrossRefPubMedGoogle Scholar
  16. 16.
    Balik V, Srovnal J, Sulla I, Kalita O, Foltanova T, Vaverka M, et al. MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas. J Neuro-Oncol. 2013;112(1):1–8. doi: 10.1007/s11060-012-1038-6.CrossRefGoogle Scholar
  17. 17.
    Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 2012;48(3):R45–53. doi: 10.1530/JME-12-0008.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Xia Y, He Z, Liu B, Wang P, Chen Y. Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway. Mol Med Rep. 2015;12(3):4530–7. doi: 10.3892/mmr.2015.3897.PubMedGoogle Scholar
  19. 19.
    Ying L, Huang Y, Chen H, Wang Y, Xia L, Chen Y, et al. Downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer. Mol BioSyst. 2013;9(3):407–11. doi: 10.1039/c2mb25386k.CrossRefPubMedGoogle Scholar
  20. 20.
    KH L, Li W, Liu XH, Sun M, Zhang ML, WQ W, et al. Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer. 2013;13:461. doi: 10.1186/1471-2407-13-461.CrossRefGoogle Scholar
  21. 21.
    Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, et al. Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. 2010;70(6):2350–8. doi: 10.1158/0008-5472.CAN-09-3885.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, et al. Activation of p53 by MEG3 non-coding RNA. J Biol Chem. 2007;282(34):24731–42. doi: 10.1074/jbc.M702029200.CrossRefPubMedGoogle Scholar
  23. 23.
    Consortium EP, Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, et al. Identification and analysis of functional elements in 1 % of the human genome by the ENCODE pilot project. Nature. 2007;447(7146):799–816. doi: 10.1038/nature05874.CrossRefGoogle Scholar
  24. 24.
    Louro R, Smirnova AS, Verjovski-Almeida S. Long intronic noncoding RNA transcription: expression noise or expression choice? Genomics. 2009;93(4):291–8. doi: 10.1016/j.ygeno.2008.11.009.CrossRefPubMedGoogle Scholar
  25. 25.
    Su X, Malouf GG, Chen Y, Zhang J, Yao H, Valero V, et al. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 2014;5(20):9864–76. doi: 10.18632/oncotarget.2454.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Khalili-Azad T, Razmkhah M, Ghiam AF, Doroudchi M, Talei AR, Mojtahedi Z, et al. Association of interleukin-18 gene promoter polymorphisms with breast cancer. Neoplasma. 2009;56(1):22–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Li Y, Wang Z, Shi H, Li H, Li L, Fang R, et al. HBXIP and LSD1 scaffolded by lncRNA Hotair mediate transcriptional activation by c-Myc. Cancer Res. 2015. doi: 10.1158/0008-5472.CAN-14-3607.Google Scholar
  28. 28.
    Anko ML, Neugebauer KM. Long noncoding RNAs add another layer to pre-mRNA splicing regulation. Mol Cell. 2010;39(6):833–4. doi: 10.1016/j.molcel.2010.09.003.CrossRefPubMedGoogle Scholar
  29. 29.
    Yan J, Guo X, Xia J, Shan T, Gu C, Liang Z, et al. MiR-148a regulates MEG3 in gastric cancer by targeting DNA methyltransferase 1. Med Oncol. 2014;31(3):879. doi: 10.1007/s12032-014-0879-6.CrossRefPubMedGoogle Scholar
  30. 30.
    Braconi C, Kogure T, Valeri N, Huang N, Nuovo G, Costinean S, et al. microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 2011;30(47):4750–6. doi: 10.1038/onc.2011.193.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Zhang J, Yao T, Wang Y, Yu J, Liu Y, Lin Z. Long noncoding RNA MEG3 is downregulated in cervical cancer and affects cell proliferation and apoptosis by regulating miR-21. Cancer Biol Ther. 2015. doi: 10.1080/15384047.2015.1108496.Google Scholar
  32. 32.
    Luo G, Wang M, Wu X, Tao D, Xiao X, Wang L, et al. Long non-coding RNA MEG3 inhibits cell proliferation and induces apoptosis in prostate cancer. Cell Physiol Biochem. 2015;37(6):2209–20. doi: 10.1159/000438577.CrossRefPubMedGoogle Scholar
  33. 33.
    Mondal T, Subhash S, Vaid R, Enroth S, Uday S, Reinius B, et al. MEG3 long noncoding RNA regulates the TGF-beta pathway genes through formation of RNA-DNA triplex structures. Nat Commun. 2015;6:7743. doi: 10.1038/ncomms8743.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Thoracic SurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
  2. 2.Department of VIP WardThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina

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