Skip to main content

Advertisement

SpringerLink
Log in

A novel long noncoding RNA-LOWEG is low expressed in gastric cancer and acts as a tumor suppressor by inhibiting cell invasion

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Long noncoding RNA (lncRNA) have been reported to be involved in the development of multiple cancers. The aim of this study was to report the identification of lncRNA-CTD-2108O9.1, which we have named lncRNA low expressed in gastric cancer (lncRNA-LOWEG), and investigate its role in cancer development.

Methods

Total RNA was extracted from the tissues of 94 patients with GC, one normal gastric epithelial cell line and four GC cell lines. Expression levels of lncRNA-LOWEG were determined by real-time PCR. Moreover, CCK-8 proliferation assay, transwell cell invasion assay and flow cytometry were performed to study the effects of lncRNA-LOWEG on SGC-7901 cell proliferation, cell invasion and cell cycle progression. Lastly, western blot and real-time PCR were used to verify the potential target genes of lncRNA-LOWEG.

Results

Significantly reduced expression of lncRNA-LOWEG was found in gastric cancer tissues and cell lines (SGC-7901, AGS, BGC-823 and HG-27) compared with patient-matched nontumorous adjacent tissues (P < 0.01) or the normal gastric cell line GES-1 (P < 0.05). Moreover, the transwell assay showed that the number of cells capable of passing through the Matrigel was significantly reduced after lncRNA-LOWEG transfection (P < 0.05). However, lncRNA-LOWEG overexpression did not significantly influence cell proliferation (P > 0.05) and cell cycle progression (P > 0.05). Lastly, western blot and real-time PCR analysis suggested that lncRNA-LOWEG is positively correlated with the expression of leukemia inhibitory factor receptor (LIFR) gene at the translational level.

Conclusions

LncRNA-LOWEG is a tumor suppressor that inhibits GC cell invasion. And LIFR gene is up-regulated by lncRNA-LOWEG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Berteaux N, Lottin S, Monte D, Pinte S, Quatannens B, Coll J, Hondermarck H, Curgy JJ, Dugimont T, Adriaenssens E (2005) H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1. J Biol Chem 280(33):29625–29636. doi:10.1074/jbc.M504033200

    Article  CAS  PubMed  Google Scholar 

  • Byun HM, Wong HL, Birnstein EA, Wolff EM, Liang G, Yang AS (2007) Examination of IGF2 and H19 loss of imprinting in bladder cancer. Cancer Res 67(22):10753–10758. doi:10.1158/0008-5472.CAN-07-0329

    Article  CAS  PubMed  Google Scholar 

  • Carrieri C, Cimatti L, Biagioli M, Beugnet A, Zucchelli S, Fedele S, Pesce E, Ferrer I, Collavin L, Santoro C, Forrest AR, Carninci P, Biffo S, Stupka E, Gustincich S (2012) Long non-coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat. Nature 491(7424):454–457. doi:10.1038/nature11508

    Article  CAS  PubMed  Google Scholar 

  • Chen D, Sun Y, Wei Y, Zhang P, Rezaeian AH, Teruya-Feldstein J, Gupta S, Liang H, Lin HK, Hung MC, Ma L (2012) LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker. Nat Med 18(10):1511–1517. doi:10.1038/nm.2940

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cheng JC, Klausen C, Leung PC (2013) Hypoxia-inducible factor 1 alpha mediates epidermal growth factor-induced down-regulation of E-cadherin expression and cell invasion in human ovarian cancer cells. Cancer Lett 329(2):197–206. doi:10.1016/j.canlet.2012.10.029

    Article  CAS  PubMed  Google Scholar 

  • Cho YG, Chang X, Park IS, Yamashita K, Shao C, Ha PK, Pai SI, Sidransky D, Kim MS (2011) Promoter methylation of leukemia inhibitory factor receptor gene in colorectal carcinoma. Int J Oncol 39(2):337–344. doi:10.3892/ijo.2011.1050

    PubMed Central  CAS  PubMed  Google Scholar 

  • de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, Levy DE, Depinho RA, Bonni A (2008) Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 22(4):449–462. doi:10.1101/gad.1606508

    Article  PubMed Central  PubMed  Google Scholar 

  • Di Gesualdo F, Capaccioli S, Lulli M (2014) A pathophysiological view of the long non-coding RNA world. Oncotarget 5(22):10976–10996

    Article  PubMed Central  PubMed  Google Scholar 

  • Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G 3rd, Kenny PJ, Wahlestedt C (2008) Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretase. Nat Med 14(7):723–730. doi:10.1038/nm1784

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fang XY, Pan HF, Leng RX, Ye DQ (2015) Long noncoding RNAs: Novel insights into gastric cancer. Cancer letters 356((2 Pt B)):357–366. doi:10.1016/j.canlet.2014.11.005

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Han Y, Ye J, Wu D, Wu P, Chen Z, Chen J, Gao S, Huang J (2014) LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition. BMC Cancer 14(1):932. doi:10.1186/1471-2407-14-932

    Article  PubMed Central  PubMed  Google Scholar 

  • Hohenberger P, Gretschel S (2003) Gastric cancer. Lancet 362(9380):305–315

    Article  PubMed  Google Scholar 

  • Hu G, Lou Z, Gupta M (2014a) The long non-coding RNA GAS5 cooperates with the eukaryotic translation initiation factor 4E to regulate c-Myc translation. PLoS One 9(9):e107016. doi:10.1371/journal.pone.0107016

    Article  PubMed Central  PubMed  Google Scholar 

  • Hu Y, Wang J, Qian J, Kong X, Tang J, Wang Y, Chen H, Hong J, Zou W, Chen Y, Xu J, Fang JY (2014b) Long Noncoding RNA GAPLINC Regulates CD44-Dependent Cell Invasiveness and Associates with Poor Prognosis of Gastric Cancer. Cancer Res 74(23):6890–6902. doi:10.1158/0008-5472.CAN-14-0686

    Article  CAS  PubMed  Google Scholar 

  • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107

    Article  PubMed  Google Scholar 

  • Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H, Yap CC, Suzuki M, Kawai J, Suzuki H, Carninci P, Hayashizaki Y, Wells C, Frith M, Ravasi T, Pang KC, Hallinan J, Mattick J, Hume DA, Lipovich L, Batalov S, Engstrom PG, Mizuno Y, Faghihi MA, Sandelin A, Chalk AM, Mottagui-Tabar S, Liang Z, Lenhard B, Wahlestedt C, Group RGER, Genome Science G, Consortium F (2005) Antisense transcription in the mammalian transcriptome. Science 309(5740):1564–1566. doi:10.1126/science.1112009

  • Kim K, Jutooru I, Chadalapaka G, Johnson G, Frank J, Burghardt R, Kim S, Safe S (2013) HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 32(13):1616–1625. doi:10.1038/onc.2012.193

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kishimoto T, Taga T, Akira S (1994) Cytokine signal transduction. Cell 76(2):253–262

    Article  CAS  PubMed  Google Scholar 

  • Kong X, Qian J, Chen LS, Wang YC, Wang JL, Chen H, Weng YR, Zhao SL, Hong J, Chen YX, Zou W, Xu J, Fang JY (2013) Synbindin in extracellular signal-regulated protein kinase spatial regulation and gastric cancer aggressiveness. J Natl Cancer Inst 105(22):1738–1749. doi:10.1093/jnci/djt271

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li H, Yu B, Li J, Su L, Yan M, Zhu Z, Liu B (2014) Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget 5(8):2318–2329

    Article  PubMed Central  PubMed  Google Scholar 

  • Luebeck EG, Curtius K, Jeon J, Hazelton WD (2013) Impact of tumor progression on cancer incidence curves. Cancer Res 73(3):1086–1096. doi:10.1158/0008-5472.CAN-12-2198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mattick JS, Makunin IV (2006) Non-coding RNA. Human molecular genetics 15 Spec No 1:R17-29 doi:10.1093/hmg/ddl046

  • Mercer TR, Dinger ME, Sunkin SM, Mehler MF, Mattick JS (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci USA 105(2):716–721. doi:10.1073/pnas.0706729105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, Abraham J, Ackerman I, Aggarwal R, Ahn SY, Ali MK, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Bahalim AN, Barker-Collo S, Barrero LH, Bartels DH, Basanez MG, Baxter A, Bell ML, Benjamin EJ, Bennett D, Bernabe E, Bhalla K, Bhandari B, Bikbov B, Bin Abdulhak A, Birbeck G, Black JA, Blencowe H, Blore JD, Blyth F, Bolliger I, Bonaventure A, Boufous S, Bourne R, Boussinesq M, Braithwaite T, Brayne C, Bridgett L, Brooker S, Brooks P, Brugha TS, Bryan-Hancock C, Bucello C, Buchbinder R, Buckle G, Budke CM, Burch M, Burney P, Burstein R, Calabria B, Campbell B, Canter CE, Carabin H, Carapetis J, Carmona L, Cella C, Charlson F, Chen H, Cheng AT, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahiya M, Dahodwala N, Damsere-Derry J, Danaei G, Davis A, De Leo D, Degenhardt L, Dellavalle R, Delossantos A, Denenberg J, Derrett S, Des Jarlais DC, Dharmaratne SD, Dherani M, Diaz-Torne C, Dolk H, Dorsey ER, Driscoll T, Duber H, Ebel B, Edmond K, Elbaz A, Ali SE, Erskine H, Erwin PJ, Espindola P, Ewoigbokhan SE, Farzadfar F, Feigin V, Felson DT, Ferrari A, Ferri CP, Fevre EM, Finucane MM, Flaxman S, Flood L, Foreman K, Forouzanfar MH, Fowkes FG, Fransen M, Freeman MK, Gabbe BJ, Gabriel SE, Gakidou E, Ganatra HA, Garcia B, Gaspari F, Gillum RF, Gmel G, Gonzalez-Medina D, Gosselin R, Grainger R, Grant B, Groeger J, Guillemin F, Gunnell D, Gupta R, Haagsma J, Hagan H, Halasa YA, Hall W, Haring D, Haro JM, Harrison JE, Havmoeller R, Hay RJ, Higashi H, Hill C, Hoen B, Hoffman H, Hotez PJ, Hoy D, Huang JJ, Ibeanusi SE, Jacobsen KH, James SL, Jarvis D, Jasrasaria R, Jayaraman S, Johns N, Jonas JB, Karthikeyan G, Kassebaum N, Kawakami N, Keren A, Khoo JP, King CH, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Laden F, Lalloo R, Laslett LL, Lathlean T, Leasher JL, Lee YY, Leigh J, Levinson D, Lim SS, Limb E, Lin JK, Lipnick M, Lipshultz SE, Liu W, Loane M, Ohno SL, Lyons R, Mabweijano J, MacIntyre MF, Malekzadeh R, Mallinger L, Manivannan S, Marcenes W, March L, Margolis DJ, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGill N, McGrath J, Medina-Mora ME, Meltzer M, Mensah GA, Merriman TR, Meyer AC, Miglioli V, Miller M, Miller TR, Mitchell PB, Mock C, Mocumbi AO, Moffitt TE, Mokdad AA, Monasta L, Montico M, Moradi-Lakeh M, Moran A, Morawska L, Mori R, Murdoch ME, Mwaniki MK, Naidoo K, Nair MN, Naldi L, Narayan KM, Nelson PK, Nelson RG, Nevitt MC, Newton CR, Nolte S, Norman P, Norman R, O’Donnell M, O’Hanlon S, Olives C, Omer SB, Ortblad K, Osborne R, Ozgediz D, Page A, Pahari B, Pandian JD, Rivero AP, Patten SB, Pearce N, Padilla RP, Perez-Ruiz F, Perico N, Pesudovs K, Phillips D, Phillips MR, Pierce K, Pion S, Polanczyk GV, Polinder S, Pope CA 3rd, Popova S, Porrini E, Pourmalek F, Prince M, Pullan RL, Ramaiah KD, Ranganathan D, Razavi H, Regan M, Rehm JT, Rein DB, Remuzzi G, Richardson K, Rivara FP, Roberts T, Robinson C, De Leon FR, Ronfani L, Room R, Rosenfeld LC, Rushton L, Sacco RL, Saha S, Sampson U, Sanchez-Riera L, Sanman E, Schwebel DC, Scott JG, Segui-Gomez M, Shahraz S, Shepard DS, Shin H, Shivakoti R, Singh D, Singh GM, Singh JA, Singleton J, Sleet DA, Sliwa K, Smith E, Smith JL, Stapelberg NJ, Steer A, Steiner T, Stolk WA, Stovner LJ, Sudfeld C, Syed S, Tamburlini G, Tavakkoli M, Taylor HR, Taylor JA, Taylor WJ, Thomas B, Thomson WM, Thurston GD, Tleyjeh IM, Tonelli M, Towbin JA, Truelsen T, Tsilimbaris MK, Ubeda C, Undurraga EA, van der Werf MJ, van Os J, Vavilala MS, Venketasubramanian N, Wang M, Wang W, Watt K, Weatherall DJ, Weinstock MA, Weintraub R, Weisskopf MG, Weissman MM, White RA, Whiteford H, Wiebe N, Wiersma ST, Wilkinson JD, Williams HC, Williams SR, Witt E, Wolfe F, Woolf AD, Wulf S, Yeh PH, Zaidi AK, Zheng ZJ, Zonies D, Lopez AD, AlMazroa MA, Memish ZA (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380(9859):2197–2223. doi:10.1016/S0140-6736(12)61689-4

    Article  PubMed  Google Scholar 

  • Okamura Y, Nomoto S, Kanda M, Li Q, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A (2010) Leukemia inhibitory factor receptor (LIFR) is detected as a novel suppressor gene of hepatocellular carcinoma using double-combination array. Cancer Lett 289(2):170–177. doi:10.1016/j.canlet.2009.08.013

    Article  CAS  PubMed  Google Scholar 

  • Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136(4):629–641. doi:10.1016/j.cell.2009.02.006

    Article  CAS  PubMed  Google Scholar 

  • Sato S, Omori Y, Katoh K, Kondo M, Kanagawa M, Miyata K, Funabiki K, Koyasu T, Kajimura N, Miyoshi T, Sawai H, Kobayashi K, Tani A, Toda T, Usukura J, Tano Y, Fujikado T, Furukawa T (2008) Pikachurin, a dystroglycan ligand, is essential for photoreceptor ribbon synapse formation. Nat Neurosci 11(8):923–931. doi:10.1038/nn.2160

    Article  CAS  PubMed  Google Scholar 

  • Tang J, Zhuo H, Zhang X, Jiang R, Ji J, Deng L, Qian X, Zhang F, Sun B (2014) A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma. Cell Death Dis 5:e1549. doi:10.1038/cddis.2014.518

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu SC, Kallin EM, Zhang Y (2010) Role of H3K27 methylation in the regulation of lncRNA expression. Cell Res 20(10):1109–1116. doi:10.1038/cr.2010.114

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xu ZY, Yu QM, Du YA, Yang LT, Dong RZ, Huang L, Yu PF, Cheng XD (2013) Knockdown of long non-coding RNA HOTAIR suppresses tumor invasion and reverses epithelial-mesenchymal transition in gastric cancer. Int J Biol Sci 9(6):587–597. doi:10.7150/ijbs.6339

    Article  PubMed Central  PubMed  Google Scholar 

  • Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F, Sun SH (2013a) Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis. Mol Cell 49(6):1083–1096. doi:10.1016/j.molcel.2013.01.010

    Article  CAS  PubMed  Google Scholar 

  • Yang F, Xue X, Bi J, Zheng L, Zhi K, Gu Y, Fang G (2013b) Long noncoding RNA CCAT1, which could be activated by c-Myc, promotes the progression of gastric carcinoma. J Cancer Res Clin Oncol 139(3):437–445. doi:10.1007/s00432-012-1324-x

    Article  CAS  PubMed  Google Scholar 

  • Yang F, Xue X, Zheng L, Bi J, Zhou Y, Zhi K, Gu Y, Fang G (2014) Long non-coding RNA GHET1 promotes gastric carcinoma cell proliferation by increasing c-Myc mRNA stability. FEBS J 281(3):802–813. doi:10.1111/febs.12625

    Article  CAS  PubMed  Google Scholar 

  • Yuan JH, Yang F, Wang F, Ma JZ, Guo YJ, Tao QF, Liu F, Pan W, Wang TT, Zhou CC, Wang SB, Wang YZ, Yang Y, Yang N, Zhou WP, Yang GS, Sun SH (2014) A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 25(5):666–681. doi:10.1016/j.ccr.2014.03.010

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Science Foundation of China (Nos. 81201888, 81372549 and No. 81172370), Specialized Research Fund for the Doctoral Program of Higher Education (No. 20122104110009) and Natural Science Foundation of Liaoning Province (No. 2014029201), Program of Education Department of Liaoning Province (L2014307).

Author information

Author notes

    Authors and Affiliations

    1. Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China

      Jun-hua Zhao, Jing-xu Sun, Yong-xi Song, Xiao-wan Chen, Yu-chong Yang, Bin Ma, Jun Wang, Peng Gao & Zhen-ning Wang

    Authors
    1. Jun-hua Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jing-xu Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yong-xi Song
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Xiao-wan Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yu-chong Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Bin Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jun Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Peng Gao
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Zhen-ning Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Zhen-ning Wang.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no competing interests.

    Ethical standards

    This study was conducted according to the principles expressed in the Declaration of Helsinki. Tissue specimens were collected after obtaining the informed consent of patients in accordance with institutional ethical guidelines, which were reviewed and approved by the Research Ethics Committee of China Medical University (Shenyang, China).

    Additional information

    Jun-hua Zhao and Jing-xu Sun have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOC 53 kb)

    Figure S1

    The effect of lncRNA-LOWEG on cell proliferation and the cell cycle. Overexpression of lncRNA-LOWEG did not cause significant differences in cell proliferation and cell cycle detection. (A) Twenty-four hours after transfection, cells were plated in 96-well plates. After 24, 48, 72 and 96 h, cell proliferation was measured using a CCK-8 assay. Data are presented as mean ± SD. Experiments were independently conducted three times to obtain the presented data. (B) Representative results of a cell cycle assay by flow cytometry 48 h after transfection. (C) Statistical results are based on four independent experiments (Mean ± SD) of cell cycle detection. (TIFF 4871 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhao, Jh., Sun, Jx., Song, Yx. et al. A novel long noncoding RNA-LOWEG is low expressed in gastric cancer and acts as a tumor suppressor by inhibiting cell invasion. J Cancer Res Clin Oncol 142, 601–609 (2016). https://doi.org/10.1007/s00432-015-2071-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00432-015-2071-6

    Keywords

    Search

    Navigation