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Decreased expression of MEG3 contributes to retinoblastoma progression and affects retinoblastoma cell growth by regulating the activity of Wnt/β-catenin pathway

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Tumor Biology

An Erratum to this article was published on 27 January 2016

Abstract

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.

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References

  1. Jabbour P, Chalouhi N, Tjoumakaris S, Gonzalez LF, Dumont AS, Chitale R, et al. Pearls and pitfalls of intraarterial chemotherapy for retinoblastoma. J Neurosurg Pediatr. 2012;10(3):175–81.

    Article  PubMed  Google Scholar 

  2. Lin P, O’Brien JM. Frontiers in the management of retinoblastoma. Am J Ophthalmol. 2009;148(2):192–8.

    Article  CAS  PubMed  Google Scholar 

  3. Gombos DS, Chevez-Barrios AP. Current treatment and management of retinoblastoma. Curr Oncol Rep. 2007;9(6):453–8.

    Article  PubMed  Google Scholar 

  4. Ponting CP, Belgard TG. Transcribed dark matter: meaning or myth? Hum Mol Genet. 2010;19(R2):R162–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Batista PJ, Chang HY. Long noncoding RNAs: cellular address codes in development and disease. Cell. 2013;152(6):1298–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cesana M, Cacchiarelli D, Legnini I, Santini T, Sthandier O, Chinappi M, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell. 2011;147(2):358–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ponting CP, Oliver PL, Reik W. Evolution and functions of long noncoding RNAs. Cell. 2009;136(4):629–41.

    Article  CAS  PubMed  Google Scholar 

  8. Taft RJ, Pang KC, Mercer TR, Dinger M, Mattick JS. Non-coding RNAs: regulators of disease. J Pathol. 2010;220(2):126–39.

    Article  CAS  PubMed  Google Scholar 

  9. Gibb EA, Brown CJ, Lam WL. The functional role of long noncoding RNA in human carcinomas. Mol Cancer. 2011;10:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wylie AA, Murphy SK, Orton TC, Jirtle RL. Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation. Genome Res. 2000;10(11):1711–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhou Y, Zhang X, Klibanski A. MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 2012;48(3):R45–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 Neurooncol. 2013;112(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang X, Zhou Y, Mehta KR, Danila DC, Scolavino S, Johnson SR, et al. A pituitary-derived MEG3 isoform functions as a growth suppressor in tumor cells. J Clin Endocrinol Metab. 2003;88(11):5119–26.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. Wang P, Ren Z, Sun P. Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation. J Cell Biochem. 2012;113(6):1868–74.

    Article  CAS  PubMed  Google Scholar 

  16. Schmidt JV, Matteson PG, Jones BK, Guan XJ, Tilghman SM. The Dlk1 and Gtl2 genes are linked and reciprocally imprinted. Genes Dev. 2000;14(16):1997–2002.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lu KH, Li W, Liu XH, Sun M, Zhang ML, Wu WQ, et al. Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer. 2013;13:461.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yin DD, Liu ZJ, Zhang E, Kong R, Zhang ZH, Guo RH. Decreased expression of long noncoding RNA MEG3 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer. Tumour Biol. 2015;36(6):4851–9.

    Article  CAS  PubMed  Google Scholar 

  19. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28.

    CAS  PubMed  Google Scholar 

  20. Benetatos L, Vartholomatos G, Hatzimichael E. MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer. 2011;129(4):773–9.

    Article  CAS  PubMed  Google Scholar 

  21. Anwar SL, Krech T, Hasemeier B, Schipper E, Schweitzer N, Vogel A, et al. Loss of imprinting and allelic switching at the DLK1-MEG3 locus in human hepatocellular carcinoma. PLoS One. 2012;7(11):e49462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Modali SD, Parekh VI, Kebebew E, Agarwal SK. Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors. Mol Endocrinol. 2015;29(2):224–37.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shi Z, Qian X, Li L, Zhang J, Zhu S, Zhu J, et al. Nuclear translocation of beta-catenin is essential for glioma cell survival. J Neuroimmune Pharmacol. 2012;7(4):892–903.

    Article  PubMed  Google Scholar 

  26. Khramtsov AI, Khramtsova GF, Tretiakova M, Huo D, Olopade OI, Goss KH. Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol. 2010;176(6):2911–20.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chung MT, Lai HC, Sytwu HK, Yan MD, Shih YL, Chang CC, et al. SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. Gynecol Oncol. 2009;112(3):646–53.

    Article  CAS  PubMed  Google Scholar 

  28. Silva AK, Yi H, Hayes SH, Seigel GM, Hackam AS. Lithium chloride regulates the proliferation of stem-like cells in retinoblastoma cell lines: a potential role for the canonical Wnt signaling pathway. Mol Vis. 2010;13(16):36–45.

    Google Scholar 

  29. Xiao W, Chen X, He M. Inhibition of the Jagged/Notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/β-catenin signaling pathways. Mol Med Rep. 2014;10(1):453–8.

    CAS  PubMed  Google Scholar 

  30. Zheng Q, Zhang Y, Ren Y, Wu Y, Yang S, Zhang Y, et al. Antiproliferative and apoptotic effects of indomethacin on human retinoblastoma cell line Y79 and the involvement of β-catenin, nuclear factor-κB and Akt signaling pathways. Ophthalmic Res. 2014;51(2):109–15.

    Article  CAS  PubMed  Google Scholar 

  31. 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/β-catenin signaling pathway. Mol Med Rep. 2015;12(3):4530–7.

    CAS  PubMed  Google Scholar 

  32. Rowe MK, Chuang DM. Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med. 2004;6(21):1–18.

    Article  PubMed  Google Scholar 

  33. Binnerts ME, Kim K-A, Bright JM, Patel SM, Tran K, Zhou M, et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6. Proc Natl Acad Sci U S A. 2007;104(37):14700–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This project was supported by the Health and Family Commission of Shenzhen Municipality Foundation (grant no. 201507010).

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Authors and Affiliations

  1. Department of Ophthalmology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, People’s Republic of China

    Yali Gao & Xiaohe Lu

  2. Department of Ophthalmology, Shenzhen People’s Hospital, Shenzhen, 518020, People’s Republic of China

    Yali Gao

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  1. Yali Gao
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  2. Xiaohe Lu
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Correspondence to Xiaohe Lu.

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An erratum to this article is available at http://dx.doi.org/10.1007/s13277-016-4831-6.

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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. Tumor Biol. 37, 1461–1469 (2016). https://doi.org/10.1007/s13277-015-4564-y

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