Advertisement

Cellular and Molecular Neurobiology

, Volume 36, Issue 7, pp 1097–1107 | Cite as

Downregulation of lncRNA-MALAT1 Affects Proliferation and the Expression of Stemness Markers in Glioma Stem Cell Line SHG139S

  • Yong Han
  • Liang Zhou
  • Tingfeng Wu
  • Yulun Huang
  • Zhe Cheng
  • Xuetao Li
  • Ting Sun
  • Youxin ZhouEmail author
  • Ziwei Du
Original Research

Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is among the most abundant and highly conserved lncRNAs, which has been detected in a wide variety of human tumors, including gastric cancer, gallbladder cancer, and so on. Previous research has showed that MALAT1 can activate LTBP3 gene in mesenchymal stem cells. However, the specific roles of MALAT1 in glioma stem cells (GSCs) remain unclear. In this study, we aimed to identify the effects of MALAT1 on proliferation and the expression of stemness markers on glioma stem cell line SHG139S. Our results showed that downregulation of MALAT1 suppressed the expression of Sox2 and Nestin which are related to stemness, while downregulation of MALAT1 promoted the proliferation in SHG139S. Further research on the underlying mechanism showed that the effects of MALAT1 downregulation on SHG139S were through regulating ERK/MAPk signaling activity. And we also found that downregulation of MALAT1 could activate ERK/MAPK signaling and promoted proliferation in SHG139 cells. These findings show that MALAT1 plays an important role in regulating the expression of stemness markers and proliferation of SHG139S, and provide a new research direction to target the progression of GSCs.

Keywords

Glioma lncRNA MALAT1 ERK/MAPK 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81372689).

Compliance with Ethical Standards

Conflict of interest

None.

References

  1. Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP (2007) CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67(9):4010–4015. doi: 10.1158/0008-5472.can-06-4180 CrossRefPubMedGoogle Scholar
  2. Bernard D, Prasanth KV, Tripathi V, Colasse S, Nakamura T, Xuan Z, Zhang MQ, Sedel F, Jourdren L, Coulpier F, Triller A, Spector DL, Bessis A (2010) A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression. The EMBO journal 29(18):3082–3093. doi: 10.1038/emboj.2010.199 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermuller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaoz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Loytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrimsdottir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, de Jong PJ (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146):799–816. doi: 10.1038/nature05874 CrossRefPubMedGoogle Scholar
  4. Braine J, Herpin F (2004) Molecular hydrogen beyond the optical edge of an isolated spiral galaxy. Nature 432(7015):369–371. doi: 10.1038/nature03054 CrossRefPubMedGoogle Scholar
  5. Chen LL, Carmichael GG (2010) Long noncoding RNAs in mammalian cells: what, where, and why? Wiley Interdiscip Rev RNA 1(1):2–21. doi: 10.1002/wrna.5 CrossRefPubMedGoogle Scholar
  6. Chen G, Li Y, Xie X, Chen J, Wu T, Li X, Wang H, Zhou Y, Du Z (2015) Establishment of a new human glioma cell line and analysis of its biological characteristics. Chin J Oncol 37(2):84–90Google Scholar
  7. Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L, Zhang X (2012) Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem 287(31):26302–26311. doi: 10.1074/jbc.M112.342113 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Gangoso E, Thirant C, Chneiweiss H, Medina JM, Tabernero A (2014) A cell-penetrating peptide based on the interaction between c-Src and connexin43 reverses glioma stem cell phenotype. Cell Death Dis 5:e1023. doi: 10.1038/cddis.2013.560 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464(7291):1071–1076. doi: 10.1038/nature08975 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Guryanova OA, Wu Q, Cheng L, Lathia JD, Huang Z, Yang J, MacSwords J, Eyler CE, McLendon RE, Heddleston JM, Shou W, Hambardzumyan D, Lee J, Hjelmeland AB, Sloan AE, Bredel M, Stark GR, Rich JN, Bao S (2011) Nonreceptor tyrosine kinase BMX maintains self-renewal and tumorigenic potential of glioblastoma stem cells by activating STAT3. Cancer Cell 19(4):498–511. doi: 10.1016/j.ccr.2011.03.004 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Gutschner T, Diederichs S (2012) The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol 9(6):703–719. doi: 10.4161/rna.20481 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Herrmann A, Cherryholmes G, Schroeder A, Phallen J, Alizadeh D, Xin H, Wang T, Lee H, Lahtz C, Swiderski P, Armstrong B, Kowolik C, Gallia GL, Lim M, Brown C, Badie B, Forman S, Kortylewski M, Jove R, Yu H (2014) TLR9 is critical for glioma stem cell maintenance and targeting. Cancer Res 74(18):5218–5228. doi: 10.1158/0008-5472.can-14-1151 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Hu L, Wu Y, Tan D, Meng H, Wang K, Bai Y, Yang K (2015) Up-regulation of long noncoding RNA MALAT1 contributes to proliferation and metastasis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res 34(1):7. doi: 10.1186/s13046-015-0123-z CrossRefPubMedPubMedCentralGoogle Scholar
  14. Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, Attardi LD, Regev A, Lander ES, Jacks T, Rinn JL (2010) A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell 142(3):409–419. doi: 10.1016/j.cell.2010.06.040 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hutchinson JN, Ensminger AW, Clemson CM, Lynch CR, Lawrence JB, Chess A (2007) A screen for nuclear transcripts identifies two linked noncoding RNAs associated with SC35 splicing domains. BMC Genom 8:39. doi: 10.1186/1471-2164-8-39 CrossRefGoogle Scholar
  16. Ji P, Diederichs S, Wang W, Boing S, Metzger R, Schneider PM, Tidow N, Brandt B, Buerger H, Bulk E, Thomas M, Berdel WE, Serve H, Muller-Tidow C (2003) MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22(39):8031–8041. doi: 10.1038/sj.onc.1206928 CrossRefPubMedGoogle Scholar
  17. Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J, Wu Q, Vasanji A, McLendon RE, Hjelmeland AB, Rich JN (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5):421–432. doi: 10.1016/j.stem.2010.02.018 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Li CH, Chen Y (2013) Targeting long non-coding RNAs in cancers: progress and prospects. Int J Biochem Cell Biol 45(8):1895–1910. doi: 10.1016/j.biocel.2013.05.030 CrossRefPubMedGoogle Scholar
  19. Li B, Chen P, Qu J, Shi L, Zhuang W, Fu J, Li J, Zhang X, Sun Y, Zhuang W (2014) Activation of LTBP3 gene by a long noncoding RNA (lncRNA) MALAT1 transcript in mesenchymal stem cells from multiple myeloma. J Biol Chem 289(42):29365–29375. doi: 10.1074/jbc.M114.572693 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Li Y, Wang H, Sun T, Chen J, Guo L, Shen H, Du Z, Zhou Y (2015) Biological characteristics of a new human glioma cell line transformed into A2B5(+) stem cells. Mol Cancer 14(1):75. doi: 10.1186/s12943-015-0343-z CrossRefPubMedPubMedCentralGoogle Scholar
  21. Lin R, Maeda S, Liu C, Karin M, Edgington TS (2007) A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas. Oncogene 26(6):851–858. doi: 10.1038/sj.onc.1209846 CrossRefPubMedGoogle Scholar
  22. Ling H, Spizzo R, Atlasi Y, Nicoloso M, Shimizu M, Redis RS, Nishida N, Gafa R, Song J, Guo Z, Ivan C, Barbarotto E, De Vries I, Zhang X, Ferracin M, Churchman M, van Galen JF, Beverloo BH, Shariati M, Haderk F, Estecio MR, Garcia-Manero G, Patijn GA, Gotley DC, Bhardwaj V, Shureiqi I, Sen S, Multani AS, Welsh J, Yamamoto K, Taniguchi I, Song MA, Gallinger S, Casey G, Thibodeau SN, Le Marchand L, Tiirikainen M, Mani SA, Zhang W, Davuluri RV, Mimori K, Mori M, Sieuwerts AM, Martens JW, Tomlinson I, Negrini M, Berindan-Neagoe I, Foekens JA, Hamilton SR, Lanza G, Kopetz S, Fodde R, Calin GA (2013) CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer. Genome Res 23(9):1446–1461. doi: 10.1101/gr.152942.112 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, Galun E (2007) The H19 non-coding RNA is essential for human tumor growth. PLoS ONE 2(9):e845. doi: 10.1371/journal.pone.0000845 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Nagano T, Fraser P (2011) No-nonsense functions for long noncoding RNAs. Cell 145(2):178–181. doi: 10.1016/j.cell.2011.03.014 CrossRefPubMedGoogle Scholar
  25. Pasmant E, Sabbagh A, Masliah-Planchon J, Ortonne N, Laurendeau I, Melin L, Ferkal S, Hernandez L, Leroy K, Valeyrie-Allanore L, Parfait B, Vidaud D, Bieche I, Lantieri L, Wolkenstein P, Vidaud M (2011) Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. J Natl Cancer Inst 103(22):1713–1722. doi: 10.1093/jnci/djr416 CrossRefPubMedGoogle Scholar
  26. Prensner JR, Sahu A, Iyer MK, Malik R, Chandler B, Asangani IA, Poliakov A, Vergara IA, Alshalalfa M, Jenkins RB, Davicioni E, Feng FY, Chinnaiyan AM (2014) The IncRNAs PCGEM1 and PRNCR1 are not implicated in castration resistant prostate cancer. Oncotarget 5(6):1434–1438CrossRefPubMedPubMedCentralGoogle Scholar
  27. Rosen JM, Jordan CT (2009) The increasing complexity of the cancer stem cell paradigm. Science 324(5935):1670–1673. doi: 10.1126/science.1171837 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Shrivastava S, Steele R, Sowadski M, Crawford SE, Varvares M, Ray RB (2015) Identification of molecular signature of head and neck cancer stem-like cells. Sci Rep 5:7819. doi: 10.1038/srep07819 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Stupp R, Tonn JC, Brada M, Pentheroudakis G (2010) High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v190–v193. doi: 10.1093/annonc/mdq187 CrossRefPubMedGoogle Scholar
  30. Sun Y, Wu J, Wu SH, Thakur A, Bollig A, Huang Y, Liao DJ (2009) Expression profile of microRNAs in c-Myc induced mouse mammary tumors. Breast Cancer Res Treat 118(1):185–196. doi: 10.1007/s10549-008-0171-6 CrossRefPubMedGoogle Scholar
  31. Szegedi K, Sonkoly E, Nagy N, Nemeth IB, Bata-Csorgo Z, Kemeny L, Dobozy A, Szell M (2010) The anti-apoptotic protein G1P3 is overexpressed in psoriasis and regulated by the non-coding RNA, PRINS. Exp Dermatol 19(3):269–278. doi: 10.1111/j.1600-0625.2010.01066.x CrossRefPubMedGoogle Scholar
  32. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA, Blencowe BJ, Prasanth SG, Prasanth KV (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39(6):925–938. doi: 10.1016/j.molcel.2010.08.011 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Vescovi AL, Galli R, Reynolds BA (2006) Brain tumour stem cells. Nat Rev Cancer 6(6):425–436. doi: 10.1038/nrc1889 CrossRefPubMedGoogle Scholar
  34. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507. doi: 10.1056/NEJMra0708126 CrossRefPubMedGoogle Scholar
  35. Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23(13):1494–1504. doi: 10.1101/gad.1800909 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Wu XS, Wang XA, Wu WG, Hu YP, Li ML, Ding Q, Weng H, Shu YJ, Liu TY, Jiang L, Cao Y, Bao RF, Mu JS, Tan ZJ, Tao F, Liu YB (2014) MALAT1 promotes the proliferation and metastasis of gallbladder cancer cells by activating the ERK/MAPK pathway. Cancer Biol Ther 15(6):806–814. doi: 10.4161/cbt.28584 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Xu C, Yang M, Tian J, Wang X, Li Z (2011) MALAT-1: a long non-coding RNA and its important 3′ end functional motif in colorectal cancer metastasis. Int J Oncol 39(1):169–175. doi: 10.3892/ijo.2011.1007 PubMedGoogle Scholar
  38. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, Dorrestein PC, Rosenfeld MG (2011) ncRNA- and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell 147(4):773–788. doi: 10.1016/j.cell.2011.08.054 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Yang TQ, Lu XJ, Wu TF, Ding DD, Zhao ZH, Chen GL, Xie XS, Li B, Wei YX, Guo LC, Zhang Y, Huang YL, Zhou YX, Du ZW (2014) MicroRNA-16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor-kappaB1/MMP9 signaling pathway. Cancer Sci 105(3):265–271. doi: 10.1111/cas.12351 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Zhang ZZ, Shen ZY, Shen YY, Xu J, Zhao EH, Wang M, Wang CJ, Cao H (2015) HOTAIR long noncoding RNA promotes gastric cancer metastasis through suppression of Poly r(C) Binding Protein (PCBP) 1. Mol Cancer Ther. doi: 10.1158/1535-7163.mct-14-0695 Google Scholar
  41. Zhou Y, Zhang X, Klibanski A (2012) MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol 48(3):R45–R53. doi: 10.1530/jme-12-0008 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yong Han
    • 1
  • Liang Zhou
    • 1
  • Tingfeng Wu
    • 1
  • Yulun Huang
    • 1
  • Zhe Cheng
    • 1
  • Xuetao Li
    • 1
  • Ting Sun
    • 1
  • Youxin Zhou
    • 1
    Email author
  • Ziwei Du
    • 1
  1. 1.Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China

Personalised recommendations