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Human Cell

pp 1–11 | Cite as

LncRNA MYCNOS facilitates proliferation and invasion in hepatocellular carcinoma by regulating miR-340

  • Junfeng Yu
  • Zhejian Ou
  • Yangyang Lei
  • Liuhua Chen
  • Qiao Su
  • Kunsong ZhangEmail author
Research Article
  • 18 Downloads

Abstract

Hepatocellular carcinoma (HCC) remains one of the most common and aggressive human cancers worldwide. Accumulating evidences indicate that non-coding RNAs are critical regulators implicated in various physiological processes including HCC development. Long non-coding RNA (lncRNA) MYCN opposite-strand (MYCNOS) was reported to be up-regulated in several human cancers, yet its role in HCC progression is still elusive. In the present study, MYCNOS was up-regulated in both HCC tissues and cell lines, and elevated MYCNOS expression was correlated to shorter survival time of HCC patients. We knocked down MYCNOS expression using short hairpin RNAs specifically targeting MYCNOS. MYCNOS knockdown significantly inhibited proliferation in HCC cells in vitro accompanied by exacerbated cell apoptosis; it also suppressed tumor growth in mouse model in vivo. Besides, the migration and invasion of HCC cells were remarkably inhibited after MYCNOS knockdown. In addition, MYCNOS acted as a negative regulator of miR-340 in HCC cells, and all effects of MYCNOS knockdown were abrogated by further miR-340 inhibition. We also discovered that oncogene phosphatidylinositol-3, 4, 5-trisphosphate-dependent Rac exchange factor 2 (PREX2) was a downstream target of miR-340, and PREX2 expression was positively correlated to that of MYCNOS in HCC tissues. In conclusion, our findings demonstrated that MYCNOS knockdown inhibited HCC progression through regulating miR-340.

Keywords

Hepatocellular carcinoma Proliferation/invasion MYCNOS MiR-340 PREX2 

Notes

Author contributions

JFY, ZJO, and KSZ conceived and designed the experiments. YYL and LHC analyzed and interpreted the results of the experiments. QS performed the experiments.

Funding

Not applicable.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests, and all authors should confirm its accuracy.

Ethics approval and consent to participate

The animal use protocol listed below has been reviewed and approved by the Animal Ethical and Welfare Committee.

Informed consent

Written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.

References

  1. 1.
    EASL-EORTC Clinical Practice Guidelines. EASL-EORTC clinical practice guidelines management of hepatocellular carcinoma. Eur J Cancer. 2012;48(5):599–641.  https://doi.org/10.1016/j.ejca.2011.12.021.CrossRefGoogle Scholar
  2. 2.
    Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118(12):3030–44.  https://doi.org/10.1002/ijc.21731.CrossRefPubMedGoogle Scholar
  3. 3.
    Okita K. Hepatocellular carcinoma. Nihon Naika Gakkai Zasshi. 2002;91(2):627–32.CrossRefGoogle Scholar
  4. 4.
    Roberts LR, Gores GJ. Hepatocellular carcinoma: molecular pathways and new therapeutic targets. Semin Liver Dis. 2005;25(2):212–25.  https://doi.org/10.1055/s-2005-871200.CrossRefPubMedGoogle Scholar
  5. 5.
    Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, et al. Differential gene expression in distinct virologic types of hepatocellular carcinoma: association with liver cirrhosis. Oncogene. 2003;22(19):3007–14.  https://doi.org/10.1038/sj.onc.1206401.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhou S, Wang J, Zhang Z. An emerging understanding of long noncoding RNAs in kidney cancer. J Cancer Res Clin Oncol. 2014;140(12):1989–95.  https://doi.org/10.1007/s00432-014-1699-y.CrossRefPubMedGoogle Scholar
  7. 7.
    Martens-Uzunova ES, Bottcher R, Croce CM, Jenster G, Visakorpi T, Calin GA. Long noncoding RNA in prostate, bladder, and kidney cancer. Eur Urol. 2014;65(6):1140–51.  https://doi.org/10.1016/j.eururo.2013.12.003.CrossRefPubMedGoogle Scholar
  8. 8.
    O’Brien EM, Selfe JL, Martins AS, Walters ZS, Shipley JM. The long non-coding RNA MYCNOS-01 regulates MYCN protein levels and affects growth of MYCN-amplified rhabdomyosarcoma and neuroblastoma cells. BMC Cancer. 2018;18(1):217.  https://doi.org/10.1186/s12885-018-4129-8.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zhao X, Li D, Pu J, Mei H, Yang D, Xiang X, et al. CTCF cooperates with noncoding RNA MYCNOS to promote neuroblastoma progression through facilitating MYCN expression. Oncogene. 2016;35(27):3565–76.  https://doi.org/10.1038/onc.2015.422.CrossRefGoogle Scholar
  10. 10.
    Vadie N, Saayman S, Lenox A, Ackley A, Clemson M, Burdach J, et al. MYCNOS functions as an antisense RNA regulating MYCN. RNA Biol. 2015;12(8):893–9.  https://doi.org/10.1080/15476286.2015.1063773.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Su Y, Qiu Y, Qiu Z, Qu P. MicroRNA networks regulate the differentiation, expansion and suppression function of myeloid-derived suppressor cells in tumor microenvironment. J Cancer. 2019;10(18):4350–6.  https://doi.org/10.7150/jca.35205.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shirmohamadi M, Eghbali E, Najjary S, Mokhtarzadeh A, Kojabad AB, Hajiasgharzadeh K, et al. Regulatory mechanisms of microRNAs in colorectal cancer and colorectal cancer stem cells. J Cell Physiol. 2019.  https://doi.org/10.1002/jcp.29042.CrossRefPubMedGoogle Scholar
  13. 13.
    Wu ZS, Wu Q, Wang CQ, Wang XN, Huang J, Zhao JJ, et al. MiR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. Cancer. 2011;117(13):2842–52.  https://doi.org/10.1002/cncr.25860.CrossRefPubMedGoogle Scholar
  14. 14.
    Zhou X, Wei M, Wang W. MicroRNA-340 suppresses osteosarcoma tumor growth and metastasis by directly targeting ROCK1. Biochem Biophys Res Commun. 2013;437(4):653–8.  https://doi.org/10.1016/j.bbrc.2013.07.033.CrossRefPubMedGoogle Scholar
  15. 15.
    Fernandez S, Risolino M, Mandia N, Talotta F, Soini Y, Incoronato M, et al. MiR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer. Oncogene. 2015;34(25):3240–50.  https://doi.org/10.1038/onc.2014.267.CrossRefPubMedGoogle Scholar
  16. 16.
    Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 2009;23(13):1494–504.  https://doi.org/10.1101/gad.1800909.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett. 2013;339(2):159–66.  https://doi.org/10.1016/j.canlet.2013.06.013.CrossRefPubMedGoogle Scholar
  18. 18.
    Qiu MT, Hu JW, Yin R, Xu L. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol. 2013;34(2):613–20.  https://doi.org/10.1007/s13277-013-0658-6.CrossRefPubMedGoogle Scholar
  19. 19.
    Wapinski O, Chang HY. Long noncoding RNAs and human disease. Trends Cell Biol. 2011;21(6):354–61.  https://doi.org/10.1016/j.tcb.2011.04.001.CrossRefPubMedGoogle Scholar
  20. 20.
    Jacobs JF, van Bokhoven H, van Leeuwen FN, Hulsbergen-van de Kaa CA, de Vries IJ, Adema GJ, et al. Regulation of MYCN expression in human neuroblastoma cells. BMC Cancer. 2009;9:239.  https://doi.org/10.1186/1471-2407-9-239.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Long J, Bai Y, Yang X, Lin J, Wang D, He L, et al. Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma. Cancer Cell Int. 2019;19:90.  https://doi.org/10.1186/s12935-019-0817-y.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Liu B, Ma T, Li Q, Wang S, Sun W, Li W, et al. Identification of a lncRNA-associated competing endogenous RNA-regulated network in clear cell renal cell carcinoma. Mol Med Rep. 2019;20(1):485–94.  https://doi.org/10.3892/mmr.2019.10290.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, et al. Sustained proliferation in cancer: mechanisms and novel therapeutic targets. Semin Cancer Biol. 2015;35(Suppl):S25–54.  https://doi.org/10.1016/j.semcancer.2015.02.006.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell. 2011;146(3):353–8.  https://doi.org/10.1016/j.cell.2011.07.014.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Yuan J, Ji H, Xiao F, Lin Z, Zhao X, Wang Z, et al. MicroRNA-340 inhibits the proliferation and invasion of hepatocellular carcinoma cells by targeting JAK1. Biochem Biophys Res Commun. 2017;483(1):578–84.  https://doi.org/10.1016/j.bbrc.2016.12.102.CrossRefPubMedGoogle Scholar
  26. 26.
    Li CH, Yen CH, Chen YF, Lee KJ, Fang CC, Zhang X, et al. Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma. Int J Cancer. 2017;140(10):2284–97.  https://doi.org/10.1002/ijc.30652.CrossRefPubMedGoogle Scholar
  27. 27.
    Lan X, Xiao F, Ding Q, Liu J, Li J, Zhang J, et al. The effect of CXCL9 on the invasion ability of hepatocellular carcinoma through up-regulation of PREX2. J Mol Histol. 2014;45(6):689–96.  https://doi.org/10.1007/s10735-014-9593-0.CrossRefPubMedGoogle Scholar

Copyright information

© Japan Human Cell Society and Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Junfeng Yu
    • 1
  • Zhejian Ou
    • 1
  • Yangyang Lei
    • 2
  • Liuhua Chen
    • 1
  • Qiao Su
    • 3
  • Kunsong Zhang
    • 1
    Email author
  1. 1.Department of Pancreatobiliary SurgeryThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  2. 2.Department of Medical UltrasoundThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  3. 3.Department of Animal Experimental CenterThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

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