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Tumor Biology

, Volume 37, Issue 1, pp 633–640 | Cite as

MALAT1-miR-124-RBG2 axis is involved in growth and invasion of HR-HPV-positive cervical cancer cells

  • Shikai Liu
  • Lili Song
  • Saitian Zeng
  • Liang Zhang
Research Article

Abstract

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT 1) is a large, infrequently spliced non-coding RNA aberrantly expressed in cervical cancer. But the molecular mechanisms of its oncogenic role are still not quite clear. The present study explored whether there is a competing endogenous RNAs (ceRNAs) mechanism involved in the oncogenic effect of MALAT1. MALAT1 expression was firstly verified in high-risk human papillomavirus (HR-HPV)-positive tumor tissues and cell lines. Its regulation over miR-124 and the downstream target of miR-124 in regulation of growth, invasion, and apoptosis of the cancer cells are also studied. Findings of this study confirmed higher MALAT1 expression in HR-HPV (+) cervical cancer. Knockdown of endogenous MALAT1 significantly reduced cell growth rate and invasion and increased cell apoptosis of Hela and siHa cells. Besides, knockdown of MALAT1 increased the expression of miRNA-124, while ectopic expression of miR-124 decreased MALAT1 expression. In addition, we also verified a direct interaction between miR-124 and 3′UTR of GRB2. MALAT1 can indirectly modulate GRB2 expression via competing miR-124. Knockdown of GRB2 reduced cell invasion and increased cell apoptosis. In conclusion, MALAT1 can promote HR-HPV (+) cancer cell growth and invasion at least partially through the MALAT1-miR-124-RBG2 axis. This finding might provide some useful evidence about the lncRNA interaction regulatory network in tumorigenesis cervical cancer.

Keywords

MALAT1 miR-124 GRB2 HR-HPV Cervical cancer 

Notes

Conflicts of interest

None

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Munagala R, Kausar H, Munjal C, Gupta RC. Withaferin a induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 2011;32:1697–705.CrossRefPubMedGoogle Scholar
  3. 3.
    Durst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A. 1983;80:3812–5.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Fu ZC, Wang FM, Cai JM. Gene expression changes in residual advanced cervical cancer after radiotherapy: indicators of poor prognosis and radioresistance? Med Sci Monit Int Med J Exp Clin Res. 2015;21:1276–87.Google Scholar
  5. 5.
    Pan D, Wei K, Ling Y, Su S, Zhu M, Chen G. The prognostic role of ki-67/mib-1 in cervical cancer: a systematic review with meta-analysis. Med Sci Monit Int Med J Exp Clin Res. 2015;21:882–9.Google Scholar
  6. 6.
    Tsai MC, Spitale RC, Chang HY. Long intergenic noncoding rnas: new links in cancer progression. Cancer Res. 2011;71:3–7.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kornienko AE, Guenzl PM, Barlow DP, Pauler FM. Gene regulation by the act of long non-coding rna transcription. BMC Biol. 2013;11:59.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Xu S, Jin C, Shen X, Ding F, Zhu J, Fu G. MicroRNAs as potential novel therapeutic targets and tools for regulating paracrine function of endothelial progenitor cells. Med Sci Monit Int Med J Exp Clin Res. 2012;18:HY27–31.Google Scholar
  9. 9.
    Jiang Y, Li Y, Fang S, Jiang B, Qin C, Xie P, et al. The role of MALAT1 correlates with HPV in cervical cancer. Oncol Lett. 2014;7:2135–41.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Guo F, Li Y, Liu Y, Wang J, Li Y, Li G. Inhibition of metastasis-associated lung adenocarcinoma transcript 1 in caski human cervical cancer cells suppresses cell proliferation and invasion. Acta Biochim Biophys Sin. 2010;42:224–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J. Mir-124 and mir-203 are epigenetically silenced tumor-suppressive micrornas in hepatocellular carcinoma. Carcinogenesis. 2010;31:766–76.CrossRefPubMedGoogle Scholar
  12. 12.
    Xia J, Wu Z, Yu C, He W, Zheng H, He Y, et al. Mir-124 inhibits cell proliferation in gastric cancer through down-regulation of sphk1. J Pathol. 2012;227:470–80.CrossRefPubMedGoogle Scholar
  13. 13.
    Wan HY, Li QQ, Zhang Y, Tian W, Li YN, Liu M, et al. MiR-124 represses vasculogenic mimicry and cell motility by targeting amotL1 in cervical cancer cells. Cancer Lett. 2014;355:148–58.CrossRefPubMedGoogle Scholar
  14. 14.
    Wu H, Zhang J. MiR-124 rs531564 polymorphism influences genetic susceptibility to cervical cancer. Int J Clin Exp Med. 2014;7:5847–51.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Wilting SM, van Boerdonk RA, Henken FE, Meijer CJ, Diosdado B, Meijer GA, et al. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer. 2010;9:167.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Liu S, Song L, Zhang L, Zeng S, Gao F. MiR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1. Biochem Biophys Res Commun. 2015;459:679–85.CrossRefPubMedGoogle Scholar
  17. 17.
    Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2014;42:D92–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Gutschner T, Hammerle M, Diederichs S. Malat1—a paradigm for long noncoding RNA function in cancer. J Mol Med. 2013;91:791–801.CrossRefPubMedGoogle Scholar
  19. 19.
    Hirata H, Hinoda Y, Shahryari V, Deng G, Nakajima K, Tabatabai ZL, et al. Long noncoding RNA MALAT1 promotes aggressive renal cell carcinoma through Ezh2 and interacts with miR-205. Cancer Res. 2015;75:1322–31.CrossRefPubMedGoogle Scholar
  20. 20.
    Shen L, Chen L, Wang Y, Jiang X, Xia H, Zhuang Z. Long noncoding RNA MALAT1 promotes brain metastasis by inducing epithelial-mesenchymal transition in lung cancer. J Neuro-Oncol. 2015;121:101–8.CrossRefGoogle Scholar
  21. 21.
    Yang MH, Hu ZY, Xu C, Xie LY, Wang XY, Chen SY, et al. MALAT1 promotes colorectal cancer cell proliferation/migration/invasion via PRKA kinase anchor protein 9. Biochim Biophys Acta. 1852;2015:166–74.Google Scholar
  22. 22.
    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;147:358–69.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Wong KY, So CC, Loong F, Chung LP, Lam WW, Liang R, et al. Epigenetic inactivation of the miR-124-1 in haematological malignancies. PLoS ONE. 2011;6, e19027.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Sastry L, Cao T, King CR. Multiple Grb2-protein complexes in human cancer cells. Int J Cancer J Int Cancer. 1997;70:208–13.CrossRefGoogle Scholar
  26. 26.
    Spangle JM, Munger K. The HPV16 E6 oncoprotein causes prolonged receptor protein tyrosine kinase signaling and enhances internalization of phosphorylated receptor species. PLoS Pathog. 2013;9, e1003237.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Belleudi F, Leone L, Purpura V, Cannella F, Scrofani C, Torrisi MR. HPV16 E5 affects the KGFR/FGFR2b-mediated epithelial growth through alteration of the receptor expression, signaling and endocytic traffic. Oncogene. 2011;30:4963–76.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Shikai Liu
    • 1
  • Lili Song
    • 1
  • Saitian Zeng
    • 1
  • Liang Zhang
    • 1
  1. 1.Cangzhou Central HospitalCangzhou CityChina

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