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A new tumor suppressor LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells

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Tumor Biology

Abstract

Growing number of long noncoding RNAs (lncRNAs) are emerging as new modulators in cancer origination and progression. A lncRNA, ADAM metallopeptidase with thrombospondin type 1 motif, 9 (ADAMTS9) antisense RNA 2 (ADAMTS9-AS2), with unknown function, is the antisense transcript of tumor suppressor ADAMTS9. In the present study, we investigated the expression pattern and functional role of ADAMTS9-AS2 in glioma by using real-time PCR and gain-/loss-of-function studies. The results showed that the ADAMTS9-AS2 expression was significantly downregulated in tumor tissues compared with normal tissues and reversely associated with tumor grade and prognosis. Multivariate analysis of the prognosis factors showed that low ADAMTS9-AS2 expression was a significant independent predictor of poor survival in glioma. Overexpression of ADAMTS9-AS2 resulted in significant inhibition of cell migration in glioma, whereas knockdown of ADAMTS9-AS2 showed the opposite effect. We also found that ADAMTS9-AS2 expression was negatively correlated with DNA methyltransferase-1 (DNMT1). In addition, DNMT1 knockdown led to remarkable enhancement of ADAMTS9-AS2 expression. By 5-aza-dC treatment, the ADAMTS9-AS2 expression was also reactivated. The results suggested that ADAMTS9-AS2 is a novel tumor suppressor modulated by DNMT1 in glioma. LncRNA ADAMTS9-AS2 may serve as a potential biomarker and therapeutic target for glioma.

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References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classifcation of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN. Malignant glioma: genetics and biology of a grave matter. Gene Dev. 2001;15:1311–33.

    Article  CAS  PubMed  Google Scholar 

  3. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458:223–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Lee JT. Epigenetic regulation by long noncoding RNAs. Science. 2012;338:1435–9.

    Article  CAS  PubMed  Google Scholar 

  5. Nagano T, Fraser P. No-nonsense functions for long noncoding RNAs. Cell. 2011;145:178–81.

    Article  CAS  PubMed  Google Scholar 

  6. Huarte M, Rinn JL. Large non-coding RNAs: missing links in cancer? Hum Mol Genet. 2010;19:152–61.

    Article  Google Scholar 

  7. Spizzo R, Almeida MI, Colombatti A, Calin GA. Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene. 2012;31:4577–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Tsai MC, Spitale RC, Chang HY. Long. Intergenic noncoding RNAs: new links in cancer progression. Cancer Res. 2011;71:3–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007;67:3963–9.

    Article  CAS  PubMed  Google Scholar 

  10. Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature. 2008;451:202–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, et al. Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J. 2013;32:1665–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Yang X, Song JH, Cheng YL, Wu WJ, Bhagat T, and Yu YT. Long non-coding RNA HNF1A-AS1 regulates proliferation and migration in oesophageal adenocarcinoma cells. Gut .2013;0:1–10.

  13. Han L, Kong R, Yin DD, Zhang EB, Xu TP, De W, et al. Low expression of long noncoding RNA GAS6-AS1 predicts a poor prognosis in patients with NSCLC. Med Oncol. 2013;30:694.

    Article  PubMed  Google Scholar 

  14. Clark ME, Kelner GS, Turbeville LA, Boyer A, Arden KC, Maki RA. ADAMTS9, a novel member of the ADAM-TS/ metallospondin gene family. Genomics. 2000;67(3):343–50.

    Article  CAS  PubMed  Google Scholar 

  15. DEMIRCAN K, GUNDUZ E, GUNDUZ M, BEDER LB, HIROHATA S, NAGATSUKA H, et al. Increased mRNA expression of ADAMTS metalloproteinases in metastatic foci of head and neck cancer. Head Neck. 2009;31:793–801.

    Article  PubMed  Google Scholar 

  16. Lo PH, Leung AC, Kwok CY, Cheung WS, Ko JM, Yang LC, et al. Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9. Oncogene. 2007;26(1):148–57.

    Article  CAS  PubMed  Google Scholar 

  17. Lung HL, Lo PH, Xie D, Apte SS, Cheung AK, Cheng Y, et al. Stanbridge and M. L. Lung: Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association with lymph node metastases in nasopharyngeal carcinoma. Int J Cancer. 2008;123(2):401–8.

    Article  CAS  PubMed  Google Scholar 

  18. Sheu JJ, Lee CH, Ko JY, Tsao GS, Wu CC, Fang CY, et al. Chromosome 3p12.3-p14.2 and 3q26.2–q26.32 are genomic markers for prognosis of advanced nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev. 2009;18(10):2709–16.

    Article  CAS  PubMed  Google Scholar 

  19. OCAK Z, ACAR M, GUNDUZ E, GUNDUZ M, DEMIRCAN K, UYETURK U, et al. Effect of hypericin on the ADAMTS-9 and ADAMTS-8 gene expression in MCF7 breast cancer cells. Eur Rev Med Pharmacol Sci. 2013;17:1185–90.

    CAS  PubMed  Google Scholar 

  20. Du W, Wang S, Zhou Q, Li X, Chu J, Chang Z, et al. ADAMTS9 is a functional tumor suppressor through inhibiting AKT/mTOR pathway and associated with poor survival in gastric cancer. Oncogene. 2013;32:3319–28.

    Article  CAS  PubMed  Google Scholar 

  21. Viapiano MS, Hockfield S, Matthews RT. BEHAB/brevican requires ADAMTS-mediated proteolytic leavage to promote glioma invasion. J Neurooncol. 2008;88:261–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Zhao ZJ, Wu QX, Cheng J, Qiu XM, Zhang JQ, Fan H. Depletion of DNMT3A suppressed cell proliferation and restored PTEN in hepatocellular carcinoma cell. J Biomed Biotechnol. 2010;2010:737535.

    PubMed Central  PubMed  Google Scholar 

  23. Lee J, Jang SJ, Benoit N, Hoque MO, Califano JA, Barry T, et al. Presence of 5-methylcytosine in CpNpG trinucleotides in the human genome. Genomics. 2010;96:67–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Han L, Zhang KL, Shi ZD, Zhang JX, Zhu JL, Zhu SJ, et al. LncRNA profile of glioblastoma reveals the potential role of LncRNAs in contributing to glioblastoma pathogenesis. Int J Oncol. 2012;40(6):2004–12.

    CAS  PubMed  Google Scholar 

  25. Li R, Qian J, Wang YY, Zhang JX, YP Y, et al. Long noncoding RNA profiles reveal three molecular subtypes in glioma. CNS Neurosci Ther. 2014;2014:1–5.

    Google Scholar 

  26. Zhang XQ, Sun S, JK Pu ACT, Lee D, Man VY, et al. Long non-coding RNA expression profiles predict clinical phenotypes in glioma. Neurobiol Dis. 2012;48:1–8.

    Article  PubMed  Google Scholar 

  27. Zhang XQ, Sun S, Lam KF, Kiang KY, Pu JK, Ho AS, et al. A long non-coding RNA signature in glioblastoma multiforme predicts survival. Neurobiol Dis. 2013;58:123–31.

    Article  CAS  PubMed  Google Scholar 

  28. JX Zhang LH, Bao ZS, Wang YY, Chen LY, Yan W, et al. HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro-Oncology. 2013;15(12):1595–603.

    Article  Google Scholar 

  29. Shi Y, Wang Y, Luan W, Wang P, Tao T, Zhang J, et al. Long non-coding RNA H19 promotes glioma cell Invasion by deriving miR-675. PLoS ONE. 2014;9:e86295.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Wang PJ, Ren ZQ, Sun PY. 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 

  31. Wahlestedt C. Natural antisense and noncoding RNA transcripts as potential drug targets. Drug Discov Today. 2006;11:503–8.

    Article  CAS  PubMed  Google Scholar 

  32. Faghihi MA, Wahlestedt C. Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol. 2009;1:637–43.

    Article  Google Scholar 

  33. Yelin R, Dahary D, Sorek R, Levanon EY, Goldstein O, Shoshan A, et al. Widespread occurrence of antisense transcription in the human genome. Nat Biotechnol. 2003;21:379–86.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cancer Center, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, 100048, China

    Jie Yao, Peiliang Geng & Yunfeng Zhu

  2. Department of Oncology, The 161th Hospital of PLA, Jiangan District, Wuhan, 430010, Hubei Province, China

    Jie Yao

  3. Department of Neurosurgery, The First Central Hospital of Tianjin, 56 Fukang Road, Tianjin, 300192, China

    Baosheng Zhou

  4. Department of Pathology, People’s Hospital of Binzhou, Binzhou, Shandong Province, China

    Jian Zhang

  5. Neurosurgery Department, Chinese PLA General Hospital, Jinan Military Command, Jinan, China

    Kang Liu & Weijie Zhu

  6. Department of Critical Care Medicine, Chinese PLA General Hospital, Beijing, 100853, China

    Weijie Zhu

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  1. Jie Yao
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  2. Baosheng Zhou
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  3. Jian Zhang
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  4. Peiliang Geng
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  5. Kang Liu
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Correspondence to Yunfeng Zhu or Weijie Zhu.

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Jie Yao, Baosheng Zhou, Jian Zhang, and Peiliang Geng are co-first author

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Yao, J., Zhou, B., Zhang, J. et al. A new tumor suppressor LncRNA ADAMTS9-AS2 is regulated by DNMT1 and inhibits migration of glioma cells. Tumor Biol. 35, 7935–7944 (2014). https://doi.org/10.1007/s13277-014-1949-2

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  • DOI: https://doi.org/10.1007/s13277-014-1949-2

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